Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use

ABSTRACT

The invention describes novel nitrosated nonsteroidal antiinflammatory drugs (NSAIDs) and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated NSAID, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated NSAID, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating gastrointestinal disorders; for facilitating wound healing; for treating and/or preventing gastrointestinal, renal and/or respiratory toxicities resulting from the use of nonsteroidal antiinflammatory compounds; for treating inflammatory disease states and/or disorders; and for treating and/or preventing ophthalmic diseases and/or disorders.

RELATED APPLICATIONS

This application claims priority under 35 USC § 119 to U.S. ApplicationNo. 60/393,111 filed Jul. 3, 2002; U.S. Application No. 60/397,979 filedJul. 24, 2002; U.S. Application No. 60/418,353 filed Oct. 16, 2002; U.S.Application No. 60/449,798 filed Feb. 26, 2003; and to U.S. ApplicationNo. 60/456,182 filed Mar. 21, 2003.

FIELD OF INVENTION

The invention describes novel nitrosated nonsteroidal antiinflammatorydrugs (NSAIDs) and pharmaceutically acceptable salts thereof, and novelcompositions comprising at least one nitrosated NSAID, and, optionally,at least one compound that donates, transfers or releases nitric oxide,stimulates endogenous synthesis of nitric oxide, elevates endogenouslevels of endothelium-derived relaxing factor or is a substrate fornitric oxide synthase, and/or at least one therapeutic agent. Theinvention also provides novel compositions comprising at least onenitrosated NSAID, and at least one compound that donates, transfers orreleases nitric oxide, elevates endogenous levels of endothelium-derivedrelaxing factor, stimulates endogenous synthesis of nitric oxide or is asubstrate for nitric oxide synthase and/or at least one therapeuticagent. The invention also provides novel kits comprising at least onenitrosated NSAID, and, optionally, at least one nitric oxide donorand/or at least one therapeutic agent. The invention also providesmethods for treating inflammation, pain and fever; for treatinggastrointestinal disorders; for facilitating wound healing; for treatingand/or preventing gastrointestinal, renal and/or respiratory toxicitiesresulting from the use of nonsteroidal antiinflammatory compounds; fortreating inflammatory disease states and/or disorders; and for treatingand/or preventing ophthalmic diseases and/or disorders.

BACKGROUND OF THE INVENTION

Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used forthe treatment of pain, inflammation; and acute and chronic inflammatorydisorders, such as, for example, osteoarthritis arthritis and rheumatoidarthritis. These compounds inhibit the activity of the enzymecyclooxygenase (COX), also known as prostaglandin G/H synthase, which isthe enzyme that converts arachidonic acid into prostanoids. The NSAIDsalso inhibit the production of other prostaglandins, especiallyprostaglandin G₂, prostaglandin H₂ and prostaglandin E₂, therebyreducing the prostaglandin-induced pain and swelling associated with theinflammation process. The chronic use of NSAIDs has been associated withadverse effects, such as gastrointestinal ulceration and renal andrespiratory toxicity. The undesirable side effects are also due to theinhibition of prostaglandin in the affected organ.

Recently two isoforms of cyclooxygenase, encoded by two distinct genes(Kujubu et al, J. Biol. Chem., 266, 12866–12872 (1991)), have beenidentified—a constitutive form, cyclooxygenase-1 (COX-1), and aninductive form, cyclooxygenase-2 (COX-2). It is thought that theantiinflammatory effects of NSAIDs are mediated by the inhibition ofCOX-2, whereas the side effects seem to be caused by the inhibition ofCOX-1. The NSAIDs currently on the market either inhibit both isoformsof COX with little selectivity for either isoform or are COX-1selective.

There is still a need in the art for novel NSAIDs that do not have theadverse side effects associated with prior art compounds. There is alsoa need for new and improved treatments of inflammatory diseases statesand disorders; and ophthalmic diseases and disorders. The invention isdirected to these, as well as other, important ends.

SUMMARY OF THE INVENTION

The invention provides novel NSAIDs that are substituted with at leastone nitrogen dioxide group (NO₂) (i.e., nitrosated). The NSAIDs can benitrosated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Thesecompounds are potent analgesics, have antiinflammatory properties andhave an unexpected potential for facilitating wound healing. The novelcompounds also have good bioavailibility, possess potent analgesic andantiinflammatory properties and have unexpected properties for reducingthe formation of gastrointestinal lesions (ulcers). The novel compoundsalso have unexpected properties in the treatment and/or prevention ofophthalmic diseases and disorders. The invention also providescompositions comprising the novel compounds described herein in apharmaceutically acceptable carrier.

The invention is also based on the discovery that administering at leastone NSAID that is substituted with at least one NO₂ group (i.e.,nitrosated), and, optionally, at least one nitric oxide donor prevents,reduces, or reverses gastrointestinal, renal and respiratory toxicityinduced by the NSAID. Nitric oxide donors include, for example,S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SPM5185, SPM 5186 and analogues thereof, and substrates of the variousisozymes of nitric oxide synthase. Thus, another embodiment of theinvention provides compositions comprising at least one nitrosated NSAIDand at least one compound that donates, transfers or releases nitricoxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO—),or as the neutral species, nitric oxide (NO.), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase. The invention also provides forsuch compositions in a pharmaceutically acceptable carrier.

Yet another embodiment of the invention provides compositions comprisingat least one NSAID, that is substituted with at least one NO₂ group(i.e., nitrosated), and, optionally, at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO—), or as the neutral species, nitricoxide (NO.), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase, and/or,optionally, at least one therapeutic agent, including but not limitedto, steroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and the like. The inventionalso provides for such compositions in a pharmaceutically acceptablecarrier.

Yet another embodiment of the invention provides methods for treatingand/or preventing inflammation, pain and fever; for decreasing and/orpreventing gastrointestinal, renal and/or respiratory toxicity resultingfrom the use of drugs such as, nonsteroidal antiinflammatory compoundsand/or cyclooxygenase-2 selective inhibitors; for treating and/orpreventing gastrointestinal disorders; and for facilitating woundhealing in a patient in need thereof which comprises administering tothe patient a therapeutically effective amount of at least one NSAIDthat is substituted with at least one NO₂ group (i.e., nitrosated), and,optionally, at least one compound that donates, transfers or releasesnitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl(NO—), or as the neutral species, nitric oxide (NO.), and/or stimulatesendogenous production of nitric oxide or EDRF in vivo and/or is asubstrate for nitric oxide synthase (i.e., NO donors). The methods canoptionally further comprise the administration of at least onetherapeutic agent, such as, for example, steroids, cyclooxygenase-2(COX-2) inhibitors, nonsteroidal antiinflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,HMG CoA inhibitors, H₂ antagonists, antineoplastic agents, antiplateletagents, thrombin inhibitors, thromboxane inhibitors, decongestants,diuretics, sedating or non-sedating anti-histamines, inducible nitricoxide synthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and mixturesof two or more thereof. In this embodiment of the invention, the methodscan involve administering the nitrosated NSAIDs, administering thenitrosated NSAIDs and NO donors, administering the nitrosated NSAIDs andtherapeutic agents, or administering the nitrosated NSAIDs, NO donors,and therapeutic agents. The nitrosated NSAIDs, nitric oxide donors,and/or therapeutic agents can be administered separately or ascomponents of the same composition in one or more pharmaceuticallyacceptable carriers.

Yet another embodiment of the invention provides methods for treatingand/or preventing inflammatory disease states and disorders in a patientin need thereof which comprises administering to the patient atherapeutically effective amount of at least one NSAID that issubstituted with at least NO₂ group (i.e., nitrosated), and, optionally,at least one compound that donates, transfers or releases nitric oxideas a charged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO—), or asthe neutral species, nitric oxide (NO.), and/or stimulates endogenousproduction of nitric oxide or EDRF in vivo and/or is a substrate fornitric oxide synthase and/or stimulates endogenous production of NO orEDRF in vivo and/or is a substrate for nitric oxide synthase (i.e., NOdonors). The methods can optionally further comprise the administrationof at least one therapeutic agent, such as, for example, steroids,cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,5-HT agonists, HMG CoA inhibitors, H₂ antagonists, antineoplasticagents, antiplatelet agents, thrombin inhibitors, thromboxaneinhibitors, decongestants, diuretics, sedating or non-sedatingantihistamines, inducible nitric oxide synthase inhibitors, opioidsanalgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and mixtures of two or more thereof. In thisembodiment of the invention, the methods can involve administering thenitrosated NSAIDs, administering the nitrosated NSAIDs and NO donors,administering the nitrosated NSAIDs and therapeutic agents, oradministering the nitrosated NSAIDs, NO donors, and therapeutic agents.The nitrosated NSAIDs, nitric oxide donors, and/or therapeutic agentscan be administered separately or as components of the same compositionin one or more pharmaceutically acceptable carriers.

Yet another embodiment of the invention provides methods for treatingand/or preventing ophthalmic diseases and disorders in a patient in needthereof which comprises administering to the patient a therapeuticallyeffective amount of at least one NSAID that is substituted with at leastNO₂ group (i.e., nitrosylated), and, optionally, at least one compoundthat donates, transfers or releases nitric oxide as a charged species,i.e., nitrosonium (NO⁺) or nitroxyl (NO—), or as the neutral species,nitric oxide (NO.), and/or stimulates endogenous production of nitricoxide or EDRF in vivo and/or is a substrate for nitric oxide synthaseand/or stimulates endogenous production of NO or EDRF in vivo and/or isa substrate for nitric oxide synthase (i.e., NO donors). In thisembodiment of the invention, the methods can involve administering thenitrosated NSAIDs or administering the nitrosated NSAIDs and NO donors.The nitrosated NSAIDs and nitric oxide donors, can be administeredseparately or as components of the same composition in one or morepharmaceutically acceptable carriers.

In yet another embodiment the invention provides kits comprising atleast one NSAID that is substituted with at least one NO₂ group (i.e.,nitrosated), and, optionally, at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO—), or as the neutral species, nitricoxide (NO.), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase. The kitcan further comprise at least one therapeutic agent, such as, forexample, steroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. The nitrosated NSAID, the nitric oxide donor and/or therapeuticagent, can be separate components in the kit or can be in the form of acomposition in the kit in one or more pharmaceutically acceptablecarriers.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the disclosure, the following terms, unless otherwiseindicated, shall be understood to have the following meanings.

“Gastrointestinal disorder” refers to any disease or disorder of theupper gastrointestinal tract of a patient including, for example,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, constipation, ulcerative colitis, peptic ulcers, stressulcers, bleeding ulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterialinfections (including, for example, a Helicobacter Pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns.

“Upper gastrointestinal tract” refers to the esophagus, the stomach, theduodenum and the jejunum.

“Ulcers” refers to lesions of the upper gastrointestinal tract liningthat are characterized by loss of tissue. Such ulcers include gastriculcers, duodenal ulcers and gastritis.

“NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

“Cardiovascular disease or disorder” refers to any cardiovasculardisease or disorder known in the art, including, but not limited to,restenosis, atherosclerosis, atherogenesis, angina, (particularlychronic, stable angina pectoris), aneurysm, ischemic disease, congestiveheart failure or pulmonary edema associated with acute myocardialinfarction, thrombosis, controlling blood pressure in hypertension(especially hypertension associated with cardiovascular surgicalprocedures), cardiac transplant atherosclerosis, myocardial infarction,hypertension, ischemia, embolism, stroke, thrombosis, venous thrombosisthromboembolism, thrombotic occlusion and reclusion, shock, coronaryplaque inflammation, thromboembolic events, platelet aggregation,platelet adhesion, smooth; muscle cell proliferation, vascular grafting,coronary artery bypass, surgery, revascularization procedures, such as,for example, angioplasty, stent placement, endarterectomy, vascularprocedures involving arteries, veins, capillaries, and the like;vascular complications associated with the use of medical devices,wounds associated with the use of medical devices, cerebrovascularischemic events, and the like. Complications associated with the use ofmedical devices may occur as a result of increased platelet deposition,activation, thrombus formation or consumption of platelets andcoagulation proteins. Such complications, which are within thedefinition of “cardiovascular disease or disorder,” include, forexample, myocardial infarction, ischemic stroke, transient ischemicstroke, thromboembolic events, pulmonary thromboembolism, cerebralthromboembolism, thrombophlebitis, thrombocytopenia, bleeding disordersand/or any other complications which occur either directly or indirectlyas a result of the foregoing disorders.

“Restenosis” is a cardiovascular disease or disorder that refers to theclosure of a peripheral or coronary artery following trauma to theartery caused by an injury such as, for example, angioplasty, balloondilation, atherectomy, laser ablation treatment or stent insertion.Restenosis can also occur following a number of invasive surgicaltechniques, such as, for example, transplant surgery, vein grafting,coronary artery bypass surgery, endarterectomy, heart transplantation,balloon angioplasty, atherectomy, laser ablation, endovascular stenting,and the like.

“Atherosclerosis” is a form of chronic vascular injury in which some ofthe normal vascular smooth muscle cells in the artery wall, whichordinarily control vascular tone regulating blood flow, change theirnature and develop “cancer-like” behavior. These vascular smooth musclecells become abnormally proliferative, secreting substances such asgrowth factors, tissue-degradation enzymes and other proteins, whichenable them to invade and spread into the inner vessel lining, blockingblood flow and making that vessel abnormally susceptible to beingcompletely blocked by local blood clotting, resulting in the death ofthe tissue served by that artery. Atherosclerotic cardiovasculardisease, coronary heart disease (also known as coronary artery diseaseor ischemic heart disease), cerebrovascular disease and peripheralvessel disease are all common manifestations of atherosclerosis and aretherefore encompassed by the terms “atherosclerosis” and“atherosclerotic disease”.

“Thromboembolic events” includes, but is not limited to, ischemicstroke, transient ischemic stroke, myocardial infarction, anginapectoris, thrombosis, thromboembolism, thrombotic occlusion andreocclusion, acute vascular events, restenosis, transient ischemicattacks, and first and subsequent thrombotic stroke. Patients who are atrisk of developing thromboembolic events, may include those with afamilial history of, or genetically predisposed to, thromboembolicdisorders, who have had ischemic stroke, transient ischemic stroke,myocardial infarction, and those with unstable angina pectoris orchronic stable angina pectoris and patients with alteredprostacyclin/thromboxane A₂ homeostasis or higher than normalthromboxane A₂ levels leading to increase risk for thromboembolism,including patients with diabetes and rheumatoid arthritis.

“Therapeutic agent” includes any therapeutic agent that can be used totreat or prevent the diseases described herein. “Therapeutic agents”include, for example, steroids, COX-2 inhibitors, nonsteroidalantiinflammatory compounds, 5-lipoxygenase inhibitors, leukotriene B₄receptor antagonists, leukotriene A₄ hydrolase inhibitors, 5-HTagonists, 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and the like. Therapeutic agentincludes the pro-drugs and pharmaceutical derivatives thereof includingbut not limited to the corresponding nitrosated and/or nitrosylatedderivatives. Although nitric oxide donors have therapeutic activity, theterm “therapeutic agent” does not include the nitric oxide donorsdescribed herein, since nitric oxide donors are separately defined.

“Cyclooxygenase-2 (COX-2) selective inhibitor” refers to a compound thatselectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. In one embodiment, the compound has acyclooxygenase-2 IC₅₀ of less than about 2 μM and a cyclooxygenase-1IC₅₀ of greater than about 5 μM, in the human whole blood COX-2 assay(as described in Brideau et al., Inflamm Res., 45: 68–74 (1996)) andalso has a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 10, and preferably of at least40. In another embodiment, the compound has a cyclooxygenase-1 IC₅₀ ofgreater than about 1 μM, and preferably of greater than 20 μM. Thecompound can also inhibit the enzyme, lipoxygenase. Such selectivityindicate an ability to reduce the incidence of common NSAID-induced sideeffects.

“Thromboxane inhibitor” refers to any compound that reversibly orirreversibly inhibits thromboxane synthesis, and includes compoundswhich are the so-called thromboxane A₂ receptor antagonists, thromboxaneA₂ antagonists, thromboxane A₂/prostaglandin endoperoxide antagonists,thromboxane receptor (TP) antagonists, thromboxane antagonists,thromboxane synthase inhibitors, and dual acting thromboxane synthaseinhibitors and thromboxane receptor antagonists. The characteristics ofthe preferred thromboxane inhibitor should include the suppression ofthromboxane A₂ formation (thromboxane synthase inhibitors) and/orblockade of thromboxane A₂ and prostaglandin H₂ platelet and vessel wall(thromboxane receptor antagonists). The effects should block plateletactivation and therefore platelet function.

“Thromboxane A₂ receptor antagonist” refers to any compound thatreversibly or irreversibly blocks the activation of any thromboxane A₂receptor.

“Thromboxane synthase inhibitor” refers to any compound that reversiblyor irreversibly inhibits the enzyme thromboxane synthesis therebyreducing the formation of thromboxane A₂. Thromboxane synthaseinhibitors may also increase the synthesis of antiaggregatoryprostaglandins including prostacyclin and prostaglandin D₂. ThromboxaneA₂ receptor antagonists and thromboxane synthase inhibitors and can beidentified using the assays described in Tai, Methods of Enzymology,Vol. 86, 110–113 (1982); Hall, Medicinal Research Reviews, 11:503–579(1991) and Coleman et al., Pharmacol Rev., 46: 205–229 (1994) andreferences therein, the disclosures of each of which are incorporated byreference herein in their entirety.

“Dual acting thromboxane receptor antagonist and thromboxane synthaseinhibitor” refers to any compound that simultaneously acts as athromboxane A₂ receptor antagonist and a thromboxane synthase inhibitor.

“Thrombin inhibitors” refers to and includes compounds that inhibithydrolytic activity of thrombin, including the catalytic conversion offibrinogen to fibrin, activation of Factor V to Va, Factor VIII toVIIIa, Factor XIII to XIIIa and platelet activation. Thrombin inhibitorsmay be identified using assays described in Lewis et al., ThrombosisResearch. 70: 173–190 (1993).

“Platelet aggregation” refers to the binding of one or more platelets toeach other. Platelet aggregation is commonly referred to in the contextof generalized atherosclerosis, not with respect to platelet adhesion onvasculature damaged as a result of physical injury during a medicalprocedure. Platelet aggregation requires platelet activation whichdepends an the interaction between the ligand and its specific plateletsurface receptor.

“Platelet activation” refers either to the change in conformation(shape) of a cell, expression of cell surface proteins (e.g., theIIb/IIIa receptor complex, loss of GPIb surface protein), and secretionof platelet derived factors (e.g., serotonin, growth factors).

“Patient” refers to animals, preferably mammals, most preferably humans,and includes males and females, and children and adults.

“Therapeutically effective amount” refers to the amount of the compoundand/or composition that is effective to achieve its intended purpose.

“Transdermal” refers to the delivery of a compound by passage throughthe skin and into the blood stream.

“Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

“Penetration enhancement” or “permeation enhancement” refers to anincrease in the permeability of the skin or mucosal tissue to a selectedpharmacologically active compound such that the rate at which thecompound permeates through the skin or mucosal tissue is increased.

“Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

“Nitric oxide adduct” or “NO adduct” refers to compounds and functionalgroups which, under physiological conditions, can donate, release and/ordirectly or indirectly transfer any of the three redox forms of nitrogenmonoxide (NO⁺, NO⁻, NO.), such that the biological activity of thenitrogen monoxide species is expressed at the intended site of action.

“Nitric oxide releasing” or “nitric oxide donating” refers to methods ofdonating, releasing and/or directly or indirectly transferring any ofthe three redox forms of nitrogen monoxide (NO⁺, NO—, NO.), such thatthe biological activity of the nitrogen monoxide species is expressed atthe intended site of action.

“Nitric oxide donor” or “NO donor” refers to compounds that donate,release and/or directly or indirectly transfer a nitrogen monoxidespecies, and/or stimulate the endogenous production of nitric oxide orendothelium-derived relaxing factor (EDRF) in vivo and/or elevateendogenous levels of nitric oxide or EDRF in vivo. “NO donor” alsoincludes compounds that are substrates for nitric oxide synthase.

“Alkyl” refers to a lower alkyl group, a haloalkyl group, a hydroxyalkylgroup, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, acycloalkyl group or a heterocyclic ring, as defined herein. An alkylgroup may also comprise one or more radical species, such as, forexample a cycloalkylalkyl group or a heterocyclicalkyl group.

“Lower alkyl” refers to branched or straight chain acyclic alkyl groupcomprising one to about ten carbon atoms (preferably one to about eightcarbon atoms, more preferably one to about six carbon atoms). Exemplarylower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl,and the like.

“Substituted lower alkyl” refers to a lower alkyl group, as definedherein, wherein one or more of the hydrogen atoms have been replacedwith one or more R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently ahydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an aminogroup, as defined herein.

“Haloalkyl” refers to a lower alkyl group, an alkenyl group, an alkynylgroup, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclicring, as defined herein, to which is appended one or more halogens, asdefined herein. Exemplary haloalkyl groups include trifluoromethyl,chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.

“Alkenyl” refers to a branched or straight chain C₂–C₁₀ hydrocarbon(preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆ hydrocarbon)that can comprise one or more carbon-carbon double bonds. Exemplaryalkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl,2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl,octen-1-yl, and the like.

“Lower alkenyl” refers to a branched or straight chain C₂–C₄ hydrocarbonthat can comprise one or two carbon-carbon double bonds.

“Substituted alkenyl” refers to a branched or straight chain C₂–C₁₀hydrocarbon (preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆hydrocarbon) which can comprise one or more carbon-carbon double bonds,wherein one or more of the hydrogen atoms have been replaced with one ormore R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently a hydroxy, an oxo,a carboxyl, a carboxamido, a halo, a cyano or an amino group, as definedherein.

“Alkynyl” refers to an unsaturated acyclic C₂–C₁₀ hydrocarbon(preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆ hydrocarbon)that can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

“Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo(3.3.0)octane, 7-oxabycyclo(2.2.1)heptyl,8-azabicyclo(3,2,1)oct-2-enyl and the like.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarboncomprising from about 3 to about 10 carbon atoms. Cycloalkyl groups canbe unsubstituted or substituted with one, two or three substituentsindependently selected from alkyl, alkoxy, amino, alkylamino,dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl,ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro.Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike.

“Heterocyclic ring or group” refers to a saturated or unsaturated cyclichydrocarbon group having about 2 to about 10 carbon atoms (preferablyabout 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms arereplaced by one or more nitrogen, oxygen and/or sulfur atoms. Sulfurmaybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial,halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylicester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester,alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido,alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolylfuryl, thienyl, 3-pyrrolinyl, 4,5,6-trihydro-2H-pyranyl, pyridinyl1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrhydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, andthe like.

“Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

“Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclicring system comprising one or two aromatic rings. Exemplary aryl groupsinclude phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl,indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclicaryl groups) can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, alkylthio,amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester,alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid,arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester,carboxamido, alkylcarboxamido carbomyl, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary substituted aryl groups includetetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl,arylsulfonyl, and the like.

“Cycloalkenyl” refers to an unsaturated cyclic C₂–C₁₀ hydrocarbon(preferably a C₂–C₈ hydrocarbon, more preferably a C₂–C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds.

“Alkylaryl” refers to an alkyl group, as defined herein, to which isappended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

“Arylalkyl” refers to an aryl radical, as defined herein, attached to analkyl radical, as defined herein. Exemplary arylalkyl groups includebenzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl, and the like.

“Arylalkenyl” refers to an aryl radical, as defined herein, attached toan alkenyl radical, as defined herein. Exemplary arylalkenyl groupsinclude styryl, propenylphenyl, and the like.

“Cycloalkylalkyl” refers to a cycloalkyl radical, as defined herein,attached to an alkyl radical, as defined herein.

“Cycloalkylalkoxy” refers to a cycloalkyl radical, as defined herein,attached to an alkoxy radical, as defined herein.

“Cycloalkylalkylthio” refers to a cycloalkyl radical, as defined herein,attached to an alkylthio radical, as defined herein.

“Heterocyclicalkyl” refers to a heterocyclic ring radical, as definedherein, attached to an alkyl radical, as defined herein.

“Arylheterocyclic ring” refers to a bi- or tricyclic ring comprised ofan aryl ring, as defined herein, appended via two adjacent carbon atomsof the aryl ring to a heterocyclic ring, as defined herein. Exemplaryarylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

“Alkylheterocyclic ring” refers to a heterocyclic ring radical, asdefined herein, attached to an alkyl radical, as defined herein.Exemplary alkylheterocyclic rings include 2-pyridylmethyl,1-methylpiperidin-2-one-3-methyl, and the like.

“Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group or a haloalkyl group, as definedherein). Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy,cyclopentyloxy, trifluoromethoxy, and the like.

“Aryloxy” refers to R₅₅O—, wherein R₅₅ is an aryl group, as definedherein. Exemplary arylkoxy groups include napthyloxy, quinolyloxy,isoquinolizinyloxy, and the like.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein.

“Lower alkylthio” refers to a lower alkyl group, as defined herein,appended to a thio group, as defined herein.

“Arylalkoxy” or “alkoxyaryl” refers to an alkoxy group, as definedherein, to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

“Alkoxyalkyl” refers to an alkoxy group, as defined herein, appended toan alkyl group, as defined herein. Exemplary alkoxyalkyl groups includemethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

“Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appendedto a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkylgroups include 4-methoxy-2-chlorobutyl and the like.

“Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

“Cycloalkylthio” refers to R₅₄S—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkylthiogroups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and thelike.

“Haloalkoxy” refers to an alkoxy group, as defined herein, in which oneor more of the hydrogen atoms on the alkoxy group are substituted withhalogens, as defined herein. Exemplary haloalkoxy groups include1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

“Hydroxy” refers to —OH.

“Oxo” refers to ═O.

“Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganic cation.

“Oxime” refers to (═N—OR₈₁) wherein R₈₁ is a hydrogen, an alkyl group,an aryl group, an alkylsulfonyl group, an arylsulfonyl group, acarboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, acarboxamido group, an alkoxyalkyl group or an alkoxyaryl group.

“Hydrazone refers to (═N—N(R₈₁))(R′₈₁))) wherein R′₈₁ is independentlyselected from R₈₁, and R₈₁ is as defined herein.

“Organic cation” refers to a positively charged organic ion. Exemplaryorganic cations include alkyl substituted ammonium cations, and thelike.

“Inorganic cation” refers to a positively charged metal ion. Exemplaryinorganic cations include Group I metal cations such as for example,sodium, potassium, and the like.

“Hydroxyalkyl” refers to a hydroxy group, as defined herein, appended toan alkyl group, as defined herein.

“Nitrate” refers to —O—NO₂.

“Nitrite” refers to —O—NO.

“Thionitrate” refers to —S—NO₂.

“Thionitrite” and “nitrosothiol” refer to —S—NO.

“Nitro” refers to the group —NO₂ and “nitrosated” refers to compoundsthat have been substituted therewith.

“Nitroso” refers to the group —NO and “nitrosylated” refers to compoundsthat have been substituted therewith.

“Nitrile” and “cyano” refer to —CN.

“Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine (C1),and/or fluorine (F).

“Amino” refers to —NH₂, an alkylamino group, a dialkylamino group, anarylamino group, a diarylamino group, an alkylarylamino group or aheterocyclic ring, as defined herein.

“Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkylamino groups include methylamino, ethylamino,butylamino, cyclohexylamino, and the like.

“Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, as definedherein.

“Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

“Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

“Alkylarylamino or arylalkylamino” refers to R₅₂R₅₅N—, wherein R₅₂ is analkyl group, as defined herein, and R₅₅ is an aryl group, as definedherein.

“Alkylarylalkylamino” refers to R₅₂R₇₉N—, wherein R₅₂ is an alkyl group,as defined herein, and R₇₉ is an arylalkyl group, as defined herein.

“Alkylcycloalkylamino” refers to R₅₂R₈₀N—, wherein R₅₂ is an alkylgroup, as defined herein, and R₈₀ is an cycloalkyl group, as definedherein.

“Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein. Exemplary aminoalkylgroups include dimethylaminopropyl, diphenylaminocyclopentyl,methylaminomethyl, and the like.

“Aminoaryl” refers to an aryl group to which is appended an alkylaminogroup, a arylamino group or an arylalkylamino group. Exemplary aminoarylgroups include anilino, N-methylanilino, N-benzylanilino, and the like.

“Thio” refers to —S—.

“Sulfinyl” refers to —S(O)—.

“Methanthial” refers to —C(S)—.

“Thial” refers to ═S.

“Sulfonyl” refers to —S(O)₂ ⁻.

“Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation, as defined herein.

“Alkylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an aryl group, as defined herein

“Sulfonic ester” refers to —S(O)₂OR₅₈; wherein R₅₈ is an alkyl group, anaryl group, or an aryl heterocyclic ring, as defined herein.

“Sulfonanido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylsulfonanido” refers to a sulfonamido group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an aryl group, as defined herein.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group, as defined herein).

“Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, as definedherein.

“Arylalkylthio” refers to an aryl group, as defined herein, appended toan alkylthio group, as defined herein.

“Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyloxy” refers to R₅₀—S(O)₂—O—, wherein R₅₀ is an alkylgroup, as defined herein.

“Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is aryl group, asdefined herein.

“Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyloxy” refers to R₅₅—S(O)₂—O—, wherein R₅₅ is an aryl group,as defined herein.

“Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₀ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein.

“Ester” refers to R₅₁C(O)O wherein R₅₁ is a hydrogen atom, an alkylgroup, an aryl group or an arylheterocyclic ring, as defined herein.

“Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, an organiccation or an inorganic cation, as defined herein.

“Carbonyl” refers to —C(O)—.

“Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkyl group, asdefined herein.

“Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylalkylcarbonyl” refers to R₅₅—R₅₂—C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Alkylarylcarbonyl” refers to R₅₂—R₅₅-C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Heterocyclicalkylcarbonyl” refer to R₇₈C(O)— wherein R₇₈ is aheterocyclicalkyl group, as defined herein.

“Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkyl group,an aryl group or an aryl heterocyclic ring, as defined herein.

“Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkyl group, asdefined herein, appended to a carboxyl group, as defined herein.

“Alkylcarboxylic ester” refers to an alkyl group, as defined herein,appended to a carboxylic ester group, as defined herein.

“Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

“Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group, asdefined herein, appended to a carboxylic ester group, as defined herein.

“Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylcarboxamido” refers to an alkyl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Arylcrboxamido” refers to an aryl group, as defined herein, appended toa carboxamido group, as defined herein.

“Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, and R₅₉ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₀ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lone pair ofelectrons, thial or oxo, and R₇₁ and R₇₂ are each independently acovalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy, an oxy or an aryl, as defined herein.

The NSAIDs that are nitrosated in accordance with the invention and/orare included in the compositions of the invention can be any of thoseknown in the art, including those exemplified below.

Despite the introduction of many new drugs, aspirin (acetylsalicylicacid) is still the most widely prescribed antiinflammatory, analgesicand antipyretic compound and is a standard for the comparison andevaluation of all other NSAIDs. Salicylic acid itself is so irritatingthat it can only be used externally. However, derivatives, particularlysalicylate esters and salts, have been prepared which provide ingestibleforms of the salicylates which have the desired antiinflammatory andother properties. In addition to aspirin, which is the acetate ester ofsalicylic acid, are the diflurophenyl derivative (diflunisal) andsalicylsalicylic acid (salsalate). Also available are the salts ofsalicylic acid, principally sodium salicylate. Sodium salicylate andaspirin are the two most commonly used preparations for systemictreatment. Other salicylates include salicylamide, sodiumthiosalicylate, choline salicylate and magnesium salicylate. Alsoavailable are combinations of choline and magnesium salicylates. Alsocontemplated for use in the present invention are 5-aminosalicylic acid(mesalamine), salicylazosulfapyridine (sulfasalazine) andmethylsalicylate.

Another group of NSAIDs are the pyrazolon derivatives, which include,for example, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,dipyrone and apazone (azapropazone).

Another group of NSAIDs are the para-aminophenol derivatives, which arethe so-called “coal tar” analgesics, including, for example, phenacetinand its active metabolite acetaminophen.

Another group of compounds for use in the present invention includeindomethacin, a methylated indole derivative, and the structurallyrelated compound sulindac.

Also contemplated is a group of compounds referred to as the fenamateswhich are derivatives of N-phenylanthranilic acid. The most well knownof these compounds is mefenamic, meclofenamic, flufenamic, tolfenamicand etofenamic acids. They are used either as the acid or aspharmaceutically acceptable salts.

Another contemplated NSAID is tolmetin which, like the other NSAIDsdiscussed herein, causes gastric erosion and prolonged bleeding time.

Another group of NSAIDs are the propionic acid derivatives. Principalmembers of this group are, for example, ibuprofen, naproxen,flurbiprofen, fenoprofen and ketoprofen. Other members of this group, inuse or study in countries outside the U.S., include, for example,fenbufen, pirprofen, oxaprozin, indoprofen and tiaprofenic acid.

Also contemplated for use in the invention is diclofenac, one of theseries of phenylacetic acid derivatives that have been developed asantiinflammatory compounds. Other NSAIDs which are contemplated assuitable in the present invention include etodolac and nabumentone.

Each of the above NSAIDs is described more fully in the literature, suchas in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 617–657; the Merck Index on CD-ROM, 13h Edition; and in U.S. Pat. Nos. 6,057,347 and 6,297,260 assigned toNitroMed Inc., the disclosures of each of which are incorporated byreference herein in their entirety.

In one embodiment, the invention describes nitrosated NSAIDs of Formula(I) and pharmaceutically acceptable salts thereof:

wherein:

-   -   R_(m) is a hydrogen or a lower alkyl group;    -   R_(n) is:

-   s is an integer of 0 or 1;-   X is:-   (1)—Y—(CR₄–C₄′)_(p)-T-(CR₄R₄′)_(p)—ONO₂;

-    wherein T is ortho, meta or para;

-   (4)—Y—(CR₄–C₄′)_(p)—V—B-T-(CR₄R₄′)_(p)—ONO₂;-   (5)—Y—(CR₄R₄′)_(p)-T-C(O)—(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (6)—Y—(CR₄R₄′)_(p)—C(Z)—(CH₂)_(q)-T-(CR₄R₄′)_(q)(CH₂)ONO₂;-   (7)—Y—(CR₄R₄′)_(p)-T-(CH₂)_(q)—V—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (8)—Y—(CR₄R₄′)_(p)—V—(CH₂)_(q)—V—(CR₄R₄′)_(q)(CH₂)—ONO₂;-   (9)—Y—(CR₄R₄′)_(o)—(W)_(q)—(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (10)—NR_(j)—O—(CH₂)_(o)—V—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (11)—NR_(j)—O(CH₂)_(o)—(W)_(q)(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (12)—O—NR_(j)—(CH₂)_(o)—(W)_(q)—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (13)—Y—(CH₂)_(o)—(W)_(q)—(CH₂)_(o)—V—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (14) —Y—(CR₄R₄′)_(p)—V—(CH₂)_(o)—(W)_(q)—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (15) —O—NR_(j)—(CH₂)_(o)—V—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (16) —Y—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)—V—(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (17)    —Y—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)—(W)_(q)—(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (18) —Y—(CR₄R₄′)_(p)-T-(CR₄R₄′)_(p)-Q′-(CR₄R₄′)_(o)—(CH₂)_(o)—ONO₂;-   (19) —Y—(CR₄R₄′)_(q)—C(Z)-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (20) —Y—(CR₄R₄′)_(p)-Q′-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (21) —Y—(CR₄R₄′)_(q)—P(O)MM′;-   (22) —Y—(CR₄R₄′)_(o)-Q′-(CR₄R₄′), —(CH₂)—ONO₂;-   (23) —Y—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)-T-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (24)    —Y—(CR₄R₄′)_(q)—(W)_(q)—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)-(CH₂)—ONO₂;-   (25) —Y—(CR₄R₄′)_(q)—V—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (26) —Y—(CR₄R₄′)_(p)-(T)_(o)—(W)_(q)—(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (27) —Y—(CR₄R₄′)_(p)—(W)_(q)-(T)_(o)—(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (28) —Y—(CR₄R₄′)_(q)—C(Z)-V—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (29)    —Y—(CR₄R₄′)_(o)—C(R₄)(ONO₂)—(CR₄R₄′)_(q)-(T)_(o)—(W)_(q)-(T)_(o)—(CR₄R₄′)_(o)—R₅;-   (30) —Y—(CR₄R₄′)_(o)—V—(CR₄R₄′)-Q′-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (31) —Y—(CR₄R₄′)_(q)C(Z)-Q′-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (32) —Y—(CR₄R₄′)_(p)—V—(CR₄R₄′)_(p)—(CH₂)—ONO₂;-   (33) —Y—(CR₄R₄′)_(p)—V—(CH₂)_(q)-(T)_(o)—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (34) —Y—(CR₄R₄′)_(p)-(T)_(o)-Q′-(T)_(o)—(CR₄R₄′)_(q)—(CH₂)—ONO₂;-   (35)    —Y—(CR₄R₄′)_(q)—C(Z)—(CR₄R₄′)_(q)—V—(CR₄R₄′)_(o)-Q′-(CR₄R₄′).—(CH₂)—ONO₂;-   (36)    —Y—(CR₄R₄′)_(q)—C(Z)—(CR₄R₄′)_(q)—(W)_(q)—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)—(CH₂)—ONO₂;-   (37) —NR_(j)—O—(CH₂)_(o)—V—(CR₄R₄′)_(o)-Q′-(CH₂)—ONO₂;-   (38) —NR_(j)—O—(CH₂)_(o)—(W)_(q)—(CR₄R₄′)_(o)-Q′-(CH₂)—ONO₂;-   (39) —O—NR_(j)—(CH₂)_(o)—(W)_(q)—(CR₄R₄′)_(o)-Q′-(CH₂)—ONO₂;-   (40) —O—NR_(j)—(CH₂)_(o)—V—(CR₄R₄′)_(o)-Q′-(CH₂)—ONO₂;-   (41)    —NR_(j)—NR_(j)—(CR₄R₄′)_(p)—(W)_(q)-(T)_(o)—(CR₄R₄′)—(CH₂)—ONO₂; or-   (42) —Y—(CR₄R₄′)_(p)—Y—C(O)—C(R_(m))(R_(n)) with the proviso that at    least one R₄ or R₄′ must be —ONO₂ or —CH₂ONO₂, and R_(m) and R_(n)    are as defined herein in Formula (I);-   (43) —Y—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)O—ONO₂; or-   (44) —Y—(CR₄R₄′)_(o)—V—(CR₄R₄′)_(o)-Q′-(CR₄R₄′)_(o)—ONO₂;

R₄ and R₄′ at each occurrence are independently a hydrogen, lower alkylgroup, —OH, —CH₂OH, —ONO₂, —NO₂ or —CH₂ONO₂; or R₄ and R₄′ takentogether with the carbon atom to which they are attached are acycloalkyl group or a heterocyclic ring;

V is O—C(O)T-, -T-C(O)—, -T-C(O)-T or T-C(O)—)C(O)-T;

W is a covalent bond or a carbonyl group;

T at each occurrence is independently an oxygen, (S(O)_(o))_(o) orNR_(j);

R_(j) is a hydrogen, an alkyl group, an aryl group a heterocyclic ring,an alkylcarbonyl group, an alkylaryl group, an alkylsulfinyl group, analkylsulfonyl group, an arylsulfinyl group, an arylsulfonyl group, asulfonamido group, a N-alkylsulfonamido group, a N,N-diarylsulfonamidogroup, a N-arylsulfonamido group, a N-alkyl-N-arylsulfonamido group, acarboxamido group or a hydroxyl group;

p at each occurrence is independently an integer from 1 to 6;

q at each occurrence is independently an integer from 1 to 3;

o at each occurrence is independently an integer from 0 to 2;

Y is oxygen or sulfur (—S—);

B is either phenyl or (CH₂)_(o);

Q′ is a cycloalkyl group, a heterocyclic ring or an aryl group;

Z is (═O), (═N—OR₅), (═N—NR₅R′₅) or (═CR₅R′₅);

M and M′ are each independently —O⁻H₃N⁺—(CR₄R′₄)_(q)—CH₂ONO₂ or-T-(CR₄R′₄)_(o)—CH₂NO₂;

R₅ and R₅′ at each occurrence are independently a hydrogen, a hydroxylgroup, an alkyl group, an aryl group, an alkylsulfonyl group, anarylsulfonyl group, a carboxylic ester, an alkylcarbonyl group, anarylcarbonyl group, a carboxamido group, an alkoxyalkyl group, analkoxyaryl group, a cycloalkyl group or a heterocyclic ring; and

with the proviso that for X in the compounds of Formulas (I) and (II):

when Y is oxygen or sulfur in Formula 1, T is —N(CH₃) and R₄ and R₄′ arehydrogen, p cannot be the integer 2;

when Y is oxygen or sulfur in Formula 1, and T is oxygen, at least oneR₄ or R₄′ must be —OH, —NO₂ or —CH₂ONO₂ or R₄ and R₄′ taken togetherwith the carbon atom to which they are attached are a cycloalkyl groupor a heterocyclic ring;

when Y is oxygen or sulfur in Formula 9, and W is a covalent bond, atleast one R₄ or R₄′ must be —OH, —ONO₂, —NO₂ or —CH₂ONO₂ or R₄ and R₄′taken together with the carbon atom to which they are attached are acycloalkyl group or a heterocyclic ring;

when Y is oxygen or sulfur in Formula 17, and W is a covalent bond, andR₄ and R₄′ are each independently a hydrogen or a lower alkyl group, Q′cannot be a phenyl group or a saturated, unsaturated or aromaticheterocyclic ring having 5 or 6 atoms, containing one to threeheteroatoms, wherein the heteroatoms are each independently nitrogen,oxygen or sulfur;

when Y is oxygen in Formula 17, and W is a covalent bond, and R₄ and R₄′are hydrogen, Q′ cannot be a cycloalkyl group;

when Y is oxygen or sulfur in Formula 20, 22 or 43, and R₄ and R₄′ areeach independently a hydrogen or a lower alkyl group, Q′ cannot be aphenyl group or a saturated, unsaturated or aromatic heterocyclic ringhaving 5 or 6 atoms, containing one to three heteroatoms, wherein theheteroatoms are each independently nitrogen, oxygen or sulfur;

when Y is oxygen in Formula 20, 22 or 43, and W is a covalent bond, andR₄ and R₄′ are hydrogen, Q′ cannot be a cycloalkyl group;

when Y is oxygen or sulfur in Formula 26 or 27, T is —N(CH₃), W is acovalent bond and R₄ and R₄′ are hydrogen, p cannot be the integer 2,and o cannot be the integer 1 in —(CR₄R′₄)_(o);

when Y is oxygen or sulfur in Formula 26 or 27, W is a covalent bond, Tis oxygen and o is the integer 1, at least one R₄ or R₄′ must be —OH,—NO₂ or —CH₂ONO₂ or R₄ and R₄′ taken together with the carbon atom towhich they are attached are a cycloalkyl group or a heterocyclic ring;and

with the further proviso that the invention does not include thecompounds of Formula (I), wherein R_(m) is a methyl group, R_(n) isstructure 12 (i.e. naproxen) of ACS registry numbers 502158-05-6,410071-57-7, 311336-65-9, 311336-63-7, 311336-62-6, 290335-27-2,290335-26-1, 290335-25-0, 174454-51-4, 170591-17-0, 163133-43-5; and thecompounds of Formula (I) wherein R_(m) is a hydrogen, R_(n) is structure16 (i.e. diclofenac) of ACS registry numbers 497818-55-0, 454170-89-9,326850-43-5, 311336-66-0, 311336-64-8, 311336-61-5, 290335-37-4,290335-36-3, 290335-35-2, 183195-09-7, 183195-07-5, 183195-06-4,183195-04-2, 174454-43-4, 156661-01-7; and the compounds of Formula (I)wherein R_(m) is a hydrogen, R_(n) is structure 8 (i.e. indomethacin) ofACS registry numbers 301838-28-8, 290335-34-1, 290335-33-0, 290335-32-9,290335-31-8, 204268-63-3, 164790-49-2, 163552-70-1 and the compounds ofACS registry numbers 497818-54-9, 497818-52-7, 410071-65-7, 410071-64-6,410071-63-5, 410071-62-4, 410071-61-3, 410071-60-2, 410071-59-9,410071-58-8, 410071-21-5, 402831-74-7, 342774-91-8, 326850-47-9,311336-60-4, 311336-58-0, 311336-57-9, 290335-34-1, 290335-33-0,290335-32-9, 290335-31-8, 290335-30-7, 290335-294, 290335-28-3,209002-879, 209002-86-8, 209002-85-7, 290902-84-6, 204633-00-1,204268-63-3, 18982-77-7, 189282-76-6, 188209-49-9, 174454-50-3,174454-47-8, 158836-71-6, 156970-87-5, 156970-86-4, and 156970-83-1.

In a preferred embodiment when X is Formula 42, R_(m) and R_(h) at eachoccurrence are the same.

In cases where multiple designations of variables that reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, B₀ would denote a covalent bond, while B₂ denotes(B—B) and (C(R₄)(R′₄))₂ denotes —C(R₄)(R′₄)—C(R₄)(R′₄)—.

Another embodiment of the invention describes nitrosated NSAIDs ofFormula (II), and pharmaceutically acceptable salts thereof:

wherein:

R_(k) is:

and X is as defined herein in Formula (I) or

-   (45) —Y—(CR₄R₄′)_(p)—Y—C(O)—R_(k) with the proviso that at least one    R₄ or R₄′ must be —ONO₂ or —CH₂ONO₂, and R_(k) is as defined herein    in Formula (II); and

with the further proviso that the invention does not include thecompounds of Formula (II) wherein R_(k) is structure 5 (i.e. aspirin) ofACS registry numbers 410071-45-3, 410071-44-2, 410071-40-8, 410071-39-5,410071-38-4, 410071-13-5, 349472-69-1, 290335-24-9, 290335-23-8,290335-22-7, 289056-41-3, 287118-97-2, 287118-96-1, 206556-93-6,190442-14-9, 190442-13-8, 190442-12-7, 190442-12-7, 190442-11-6,188025-64-1, 184644-94-8, 184644-92-6, 184644-90-4, 177598-18-4,177598-17-3, 177598-13-9, 177598-12-8, 175033-36-0, 171781-26-3,154424-73-4, 145585-70-2, 140218-52-6 and 140218-49-1; and the compoundsof ACS registry numbers 478163-51-8, 410071-48-6, 410071-47-5,410071-46-4, 410071-43-1, 410071-42-0, 410071-41-9, 410071-37-3,410071-36-2, 410071-35-1, 410071-34-0, 410071-33-9, 401916-64-1,302606-04-8, 257626-09-8, 257626-08-7, 256499-26-0, 209002-97-9,204268-65-5, 203563-95-5, 177598-09-3, 164790-48-1 and 163385-76-0.

In a preferred embodiment when X is Formula 45, R_(k) at each occurrenceis the same.

In another embodiment, the compounds of Formula (I) and (H) do notinclude the compounds disclosed in, for example, U.S. Pat. Nos.5,859,053, 6,429,223, 6,355,666, 6,436,990, 6,525,098, 6,552,078; and inU.S. Application Nos. 2002/0028845, 2003/0088111, and in WO 94/03421, WO94/04484, WO 94/12463, WO 95/09831, WO 95/30641, WO 96/34848, WO97/04757, WO 97/16405, WO 98/09948, WO 98/17673, WO 98/25918, WO00/44705, WO 00/51988, WO 00/61537, WO 00/61541, WO 00/72838, WO01/04082, WO 01/10814, WO 01/12584, WO 01/49275, WO 01/66088, WO02/00167, WO 02/092072, WO 02/11706, WO 02/11707, WO 02/30866, WO02/30867, WO 02/100400, WO 03/000642, WO 03/000643, WO 03/013499, WO03/022249; and in EP 0738706 B1, EO 0440098 A1; and in Endres et al.,Eur. J. Med. Chem. 34: 895-901 (1999); Gilmer et al., Eur. J. PharmSci., 16: 297–304 (2002), Gilmer et al., Eur. J. Pharm Sci., 14: 221–227(2001); and Ingram et al., J. Pharm Pharmacol., 53: 345–350 (2001); thedisclosures of each of which are incorporated by reference herein intheir entirety.

Compounds of the invention that have one or more asymmetric carbon atomsmay exist as the optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. The invention includes within its scope all such isomers andmixtures thereof.

In one embodiment of the invention, the NSAID of Formula I substitutedwith at least one NO₂ group are nitrosated derivatives of acemetacin,aceclofenac, alclofenac, alminoprofen, amfenac, bendazac, benoxaprofen,bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin, clopirac,diclofenac, etodolac, felbinac, fenclozic acid, fenbufen, fenoprofen,fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen,indomethacin, isofezolac, isoxepac, indoprofen, ketoprofen, lonazolac,loxoprofen, metiazinic acid, mofezolac, miroprofen, naproxen, oxaprozin,pirozolac, pirprofen, pranoprofen, protizinic acid, salicylamideO-acetic acid, sulindac, suprofen, suxibuzone, tiaprofenic acid,tolmetin, xenbucin, ximoprofen, zaltoprofen or zomepirac and the NSAIDof Formula II substituted with at least one NO₂ group are nitrosatedderivatives of aspirin, acemetcin, bumadizon, carprofenac, clidanac,diflunisal, enfenamic acid, fendosal, flufenamic acid, flunixin,gentisic acid, ketorolac, meclofenamic acid, mefenamic acid, mesalamine,niflumic acid, salsalate, tolfenamic acid or tropensin.

In preferred embodiments for the compounds of Formula (I) or (II) andpharmaceutically acceptable salts thereof, X is:

wherein:

Y′ is oxygen or sulfur;

T′ is oxygen, sulfur or NR₆;

X₅ is oxygen, (S(O)_(o))_(o) or NR₆;

R₆ is a hydrogen, a lower alkyl group, an aryl group;

R₇ is a lower alkyl group or an aryl group;

R₈ at each occurrence is independently is a hydrogen, a hydroxyl group,a lower alkyl group, an aryl group, —NO₂, —CH₂—ONO₂ or —CH₂—OH;

n′ and m′ are each independently an integer from 0 to 10;

o is as defined herein; and

with the proviso for Formula 8 for X:

Y′ and X₅ cannot be oxygen; and

when Y′ is oxygen and X₅ is —N(CH₃), then n′ and m′ must be any integerexcept 1.

In more preferred embodiments the compounds of Formulas (I) are:

-   2-(2-(nitrooxy)ethylthio)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-((2-(nitrooxy)ethyl)sulfonyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-((2-(nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-((2-(nitrooxy)ethyl)4-nitrophenyl)amino)ethyl    2-(6-methoxy-2-naphthyl)propanoate;-   2R)-2,3-bis(nitrooxy)propyl(2S)-2(6-methoxy(2-naphthyl)propanoate;-   (2R)-7-(nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl(2S)-2-(6-methoxy    (2-naphthyl))propanoate;-   phosphonomethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate3-(nitrooxy)propylamine    nitric acid salt;-   phosphonomethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate4-nitro-1-(nitrooxy)-2-((nitrooxy)methyl)but-2-ylamine    salt;-   (5-((nitrooxy)methyl-1,3-dioxan-5-yl)methyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate;-   2,2-bis(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   3-(4-((nitrooxy)methyl)phenylcarbonyloxy)-2-oxopropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-methyl-2-nitro-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-nitro-3-(nitrooxy)-2-((nitrooxy)methyl)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-(N-(2-(nitrooxy)ethyl)carbamoyloxy)ethyl    (2S)-2-(6-methoxy(2-naphthyl))propanoate;-   3-(2-(nitrooxy)ethoxy)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate;-   4-(2-(nitrooxy)ethoxy)phenyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (N-methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (N-ethyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-(4-((nitrooxy)methyl)piperidyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (N-methyl-N-(((2-(nitrooxy)ethyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (N-methyl-N-(((3-(nitrooxy)propyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (N-methyl-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   ((2-(nitrooxy)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate;-   (N-(3-(nitrooxy)propyl)carbamoyl)methyl2-(6-methoxy-2-naphthyl)propanoate;-   ((2-((2-(nitrooxy)ethyl)sulfonyl)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate;-   1S, 5S, 2R,    6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl)oxycarbonyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (2S)-2,3-bis(nitrooxy)propyl(2S)-2-(6-methoxy-5-nitro(2-naphthyl))propanoate;-   2S)-2-hydroxy-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (2R)-2-hydroxy-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (2S)-2-(6-methoxy(2-naphthyl))-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methoxy)propanamide;-   3-(2-(4-((nitrooxy)methyl)phenyl)acetyloxy)-2-oxopropyl    (2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-(4-(2-(nitrooxy)ethyl)piperidyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   4-((2-(nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-((2-(nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate;-   (N-methyl-N-(3-(nitrooxy)propyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (2S)-2-(6-methoxy(2-naphthyl))-N-(2-(4-((nitrooxy)methyl)piperidyl)-2-oxoethoxy)propanamide;-   3-((2-(nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate;-   2-(4-(2-(nitrooxy)ethyl)piperazinyl)-2-oxoethyl    (2S)-2-(6-methoxy(2-naphthyl))propanoate hydrogen chloride;-   3-((2S)-2-(6-methoxy(2-naphthyl)propanoyloxy)-2-methyl-2-((nitrooxy)methyl)propyl(2S)-2-(6-methoxy(2-naphthyl)propanoate;-   2-(4-(2-(nitrooxy)ethoxy)phenoxy)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-((2S)-2-(6-methoxy(2-naphthyl))propanoyloxy)ethyl    3-(nitrooxy)-propyl ethane-1,2-dioate;-   N-((2S)-2-(6-methoxy(2-naphthyl))propanoylamino)-4(nitrooxy)butanamide;-   4-((2S)-2-(6-methoxy(2-naphthyl))propanoyloxy)(2S,3S)-2,3-bis(nitrooxy)butyl(2S)-2-(6-methoxy(2-naphthyl))propanoate-   (2S,3S)-2,3-bis(nitrooxy)-4-hydroxybutyl(2S)-2-(6-methyoxy(2-naphthyl))propanoate;-   2-((3-((nitrooxy)methyl)phenyl)carbonylamino)ethyl(2S)-2-(6-methoxy(2-napthyl    propanoate;-   (2R)-2-(nitrooxy)-3-(phenylmethoxy)propyl    (2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-(N-methyl(4-((nitrooxy)methyl)phenyl)carbonylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (1S,2S,5S,6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl    2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate;-   (1S,2S,5S,6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl    2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;-   2-(((4-methylphenyl)sulfonyl)(2-(nitrooxy)ethyl)amino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   2-(N-methyl-2-(4-((nitrooxy)methyl)phenyl)acetylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;-   (2R)-2,3-bis(nitrooxy)propyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate;-   (2S)-2,3-bis(nitrooxy)propyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate;-   (2S)2,3-bis(nitrooxy)propyl2    (2-((2,6-dichlorophenyl)amino)phenylacetate-   (2R)-2,3-bis(nitrooxy)propyl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;-   (2S)-2-(6-methoxy(2-naphthyl))-1-(4-(nitrooxy)butylthio)propan-1-one;-   (N-methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate;-   (N-(2-(nitrooxy)ethyl)carbamoyl)methyl    2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate;-   (N-(2-(nitrooxy)ethyl)carbamoyl)methyl 2-(2-((2,6-dichlorophenyl)    amino)phenyl)acetate; and    pharmaceutically acceptabl;e salts thereof.

Another embodiment of the invention describes the metabolites of thecompounds of Formulas (I), (II) and pharmaceutically acceptable saltsthereof. These metabolites, include but are not limited to, thenon-nitrosated derivatives, degradation products, hydrolysis products,and the like, of the compounds of Formulas (I), (II) andpharmaceutically acceptable salts thereof.

Another embodiment of the invention provides processes for making thenovel compounds of the invention and to the intermediates useful in suchprocesses. The reactions are performed in solvents appropriate to thereagents and materials used are suitable for the transformations beingeffected. It is understood by one skilled in the art of organicsynthesis that the functionality present in the molecule must beconsistent with the chemical transformation proposed. This will, onoccasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999).

The chemical reactions described herein are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by oneskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

The NSAIDs of the invention can be nitrosated through one or more sitessuch as oxygen, sulfur and/or nitrogen using the methods described inthe examples herein and using conventional methods known to one skilledin the art. For example, known methods for nitrosating compounds aredescribed in U.S. Pat. Nos. 5,380,758, 5,859,053, 5,703,073 and6,297,260; and in WO 94/03421, WO 94/04484, WO 94/12463, WO 95/09831, WO95/30641, WO 97/27749, WO 98/19672, WO 01/00563, WO 00/51988, WO00/72838, WO 01/04082, WO 01/10814, WO 01/45703, WO 02/11707, WO02/30866 and Oae et al, Org. Prep. Proc. Int., 15(3):165–198 (1983), thedisclosures of each of which are incorporated by reference herein intheir entirety. The methods of nitrosating the compounds described inthe examples herein and in these references can be applied by oneskilled in the art to produce any of the nitrosated NSAIDs describedherein.

The compounds of the invention include the NSAIDs that have beennitrosated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Thenitrosated NSAIDs of the invention donate, transfer or release abiologically active form of nitrogen monoxide (i.e., nitric oxide).

Nitrogen monoxide can exist in three forms: NO— (nitroxyl), NO.(uncharged nitric oxide) and NO⁺ (nitrosonium). NO. is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO.),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO— arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

Compounds contemplated for use in the invention (e.g., NSAIDs that arenitrosated), are, optionally, used in combination with nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer a biologically active form of nitrogen monoxide to asite of its intended activity, such as on a cell membrane in vivo.

The term “nitric oxide” encompasses uncharged nitric oxide (NO.) andcharged nitrogen monoxide species, preferably charged nitrogen monoxidespecies, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO—). Thereactive form of nitric oxide can be provided by gaseous nitric oxide.The nitrogen monoxide releasing, delivering or transferring compoundshave the structure F—NO, wherein F is a nitrogen monoxide releasing,delivering or transferring moiety, and include any and all suchcompounds which provide nitrogen monoxide to its intended site of actionin a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamide (FK-409),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamines, N-((2Z,3E)-4-ethyl-2-(hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3-pyridinecarboxamide(FR 146801), nitrosoamines, furoxans as well as substrates for theendogenous enzymes which synthesize nitric oxide. NONOates include, butare not limited to,(Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino))diazen-1-ium-1,2-diolate(“MAHMA/NO”),(Z)-1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate(“PAPA/NO”),(Z)-1-(N-(3-aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino)diazen-1-ium-1,2-diolate (spermine NONOate or “SPER/NO”) andsodium(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamineNONOate or “DEA/NO”) and derivatives thereof. NONOates are alsodescribed in U.S. Pat. Nos. 6,232,336, 5,910,316 and 5,650,447, thedisclosures of each of which are incorporated by reference herein intheir entirety.

The “NO adducts” can be mono-nitrosylated, poly-nitrosylated,mono-nitrosated and/or poly-nitrosated at a variety of naturallysusceptible or artificially provided binding sites for biologicallyactive forms of nitrogen monoxide.

One group of NO adducts is the S-nitrosothiols, which are compounds thatinclude at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated modifiedand unmodified oligonucleotides (preferably of at least 5, and morepreferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165–198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

Another embodiment of the invention is S-nitroso amino acids where thenitroso group is linked to a sulfur group of a sulfur-containing aminoacid or derivative thereof. Such compounds include, for example,S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine,and the like.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur groups on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins; heme proteins,such as hemoglobin and serum albumin; and biologically protectiveproteins, such as immunoglobulins, antibodies and cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

Other examples of suitable S-nitrosothiols include:

(i) HS(C(R_(e))(R_(f)))_(m)SNO;

(ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); or

(iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

wherein m is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic: acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, -T-Q-, or—(C(R_(g))(R_(h)))_(k)-T-Q or R_(e) and R_(f) taken together are an oxo,a thial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazoneor a bridged cycloalkyl group; Q is —NO or —NO₂; and T is independentlya covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—,wherein o is an integer from 0 to 2, R_(a) is a lone pair of electrons,a hydrogen or an alkyl group; R_(i) is a hydrogen, an alkyl, an aryl, analkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester,an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, analkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl,an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, acarboxylic ester, an aminoalkyl, an aminoaryl,—CH₂—C(T-Q)(R_(g))(R_(h)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic orinorganic cation; with the proviso that when R_(i) is—CH₂—C(T-Q)(R_(g))(R_(h)) or —(N₂O₂—).M⁺; then “-T-Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group; and

R_(g) and R_(h) at each occurrence are independently R_(e);

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(i) can be a substituenton any disubstituted nitrogen contained within the radical wherein R_(i)is as defined herein.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

Another group of NO adducts for use in the invention, where the NOadduct is a compound that donates, transfers or releases nitric oxide,include compounds comprising at least one ON—O— or ON—N— group. Thecompounds that include at least one ON—O— or ON—N— group are preferablyON—O— or ON—N-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); ON—O— or ON—N-amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixtures);ON—O— or ON—N-sugars; ON—O— or —ON—N— modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5-200nucleotides); ON—O— or ON—N— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O—, ON—N— or ON—C-heterocyclic compounds.

Another group of NO adducts for use in the invention include nitratesthat donate, transfer or release nitric oxide, such as compoundscomprising at least one O₂N—O—, O₂N—N— or O₂N—S— group. Preferred amongthese compounds are O₂N—O—, O₂N—N— or O₂N—S— polypeptides (the term“polypeptide” includes proteins and also polyamino acids that do notpossess an ascertained biological function, and derivatives thereof);O₂N—O—, O₂N—N— or O₂N—S— amino acids (including natural and syntheticamino acids and their stereoisomers and racemic mixtures); O₂N—O—,O₂N—N— or O₂N—S— sugars; O₂N—O—, O₂N—N— or O₂N—S— modified andunmodified oligonucleotides (comprising at least 5 nucleotides,preferably 5–200 nucleotides); O₂N—O—, O₂N—N— or O₂N—S— straight orbranched, saturated or unsaturated, aliphatic or aromatic, substitutedor unsubstituted hydrocarbons; and O₂N—O—, O₂N—N— or O₂N—S— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group include isosorbide dinitrate, isosorbidemononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate,nitroglycerin, pentaerythritoltetranitrate, pentrinitrol,propatylnitrate and organic nitrates with a sulfhydryl-containing aminoacid such as, for example SPM 3672, SPM 5185, SPM 5186 and thosedisclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661,129, 5,807,847and 5,883,122 and in WO 97/46521, WO 00/54756 and in WO 03/013432, thedisclosures of each of which are incorporated by reference herein intheir entirety.

Another group of NO adducts are N-oxo-N-nitrosoamines that donate,transfer or release nitric oxide and are represented by the formula:R^(1″)R^(2″)N—N(O-M⁺)—NO, where R^(1″) and R^(2″) are each independentlya polypeptide, an amino acid, a sugar, a modified or unmodifiedoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or aheterocyclic group, and where M⁺ is an organic or inorganic cation, suchas, for example, an alkyl substituted ammonium cation or a Group I metalcation.

The invention is also directed to compounds that stimulate endogenous NOor elevate levels of endogenous endothelium-derived relaxing factor(EDRF) in vivo or are substrates for nitric oxide synthase. Suchcompounds include, for example, L-arginine L-homoarginine, andN-hydroxy-L-arginine, including their nitrosated and nitrosylatedanalogs (e.g., nitrosated L-arginine, nitrosylated L-arginine,nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,nitrosated L-homoarginine and nitrosylated L-homoarginine), precursorsof L-arginine and/or physiologically acceptable salts thereof,including, for example, citrulline, ornithine, glutamine, lysine,polypeptides comprising at least one of these amino acids, inhibitors ofthe enzyme arginase (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid), nitric oxide mediators and/orphysiologically acceptable salts thereof, including, for example,pyruvate, pyruvate precursors, α-keto acids having four or more carbonatoms, precursors of α-keto acids having four or more carbon atoms (asdisclosed in WO 03/017996, the disclosure of which is incorporatedherein in its entirety), and the substrates for nitric oxide synthase,cytokines, adenosin, bradykinin, calreticulin, bisacodyl, andphenolphthalein. EDRF is a vascular relaxing factor secreted by theendothelium, and has been identified as nitric oxide (NO) or a closelyrelated derivative thereof (Palmer et al, Nature, 327:524–526 (1987);Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265–9269 (1987)).

The invention is also based on the discovery that compounds andcompositions of the invention may be used in conjunction with othertherapeutic agents for co-therapies, partially or completely, in placeof other conventional antiinflammatory compounds, such as, for example,together with steroids, COX-2 inhibitors, NSAIDs, 5-lipoxygenase (5-LO)inhibitors, leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄(LTA₄) hydrolase inhibitors, 5-HT agonists, MG-CoA inhibitors, H₂receptor antagonists, antineoplastic agents, antiplatelet agents,thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics,sedating or non-sedating anti-histamines, inducible nitric oxidesynthase inhibitors, opiods, analgesics, Helicobacter pylori inhibitors,proton pump inhibitors, isoprostane inhibitors, and mixtures of two ormore thereof.

Leukotriene A₄ (LTA₄) hydrolase inhibitors refer to compounds thatselectively inhibit leukotriene A₄ hydrolase with an IC₅₀ of less thanabout 10/M, and preferably with an IC₅₀ of less than about 1 μM.Suitable LTA₄ hydrolase inhibitors include, but are not limited to,RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acidbenzyl ester,N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine,7-(4-(4-ureidobenzyl)phenyl) heptanoic acid and 3(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt, andmixtures of two or more thereof.

Suitable LTB₄ receptor antagonists include, but are not limited to,ebselen, linazolast, ontazolast; WAY 121006; Bay-x-1005; BI-RM-270;CGS-25019C; ETH-615; MAFP; TMK-688; T-0757; LY 213024, LY 210073, LY223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111;ONO-LB457, ONO-4057, and ONO-LB-448, S-2474, calcitrol; PF 10042; Pfizer105696; RP 66153; SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228;SB-201146 and SB-209247; SKF-104493; SM 15178; TMK-688; BPC 15, andmixtures of two or more thereof. The preferred LTB₄ receptor antagonistsare calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-293111,ONO-4057 and TMK-688, and mixtures of two or more thereof.

Suitable 5-LO inhibitors include, but are not limited to, A-76745, 78773and ABT761; Bay-x-1005; CMI-392; E-3040; EF-40; F-1322; ML-3000;PF-5901; R-840; rilopirox, flobufen, linasolast, lonapolene, masoprocol,ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox,flezelastine hydrochloride, enazadrerim phosphate, and bunaprolast, andmixtures of two or more thereof. Suitable 5-LO inhibitors are alsodescribed more fully in WO 97/29776, the disclosure of which isincorporated herein by reference in its entirety.

Suitable 5-HT agonists, include, but are not limited to, rizatriptan,sumatriptan, naratriptan, zolmitroptan, cleptriptan, almotriptan, ergotalkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS 31416. Suitable5-HT agonists are described more fully in WO 0025779, and in WO00/48583. 5-HT agonists refers to a compound that is an agonist to any5-HT receptor, including but not limited to, 5-HT₁ agonists, S-HT_(1B)agonists and 5-HT_(1D) agonists, and the like.

Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, 13^(th) Edition.

Suitable HMG CoA inhibitors, include, but are not limited to, reductaseand synthase inhibitors, such as, for example, squalene synthetaseinhibitors, benzodiazepine squalene synthase inhibitors, squaleneepoxidase inhibitors, acyl-coenzyme A, bile acid sequestrants,cholesterol absorption inhibitors, and the like. Suitable HMG CoAinhibitors include simvastatin, pravastatin, lovastatin, mevastatin,fluvastatin, atorvastatin, cerivastatin, and the like, and are describedmore fully in U.S. Pat. No. 6,245,797 and WO 99/20110, the disclosuresof each of which are incorporated by reference herein in their entirety.

Suitable COX-2 inhibitors, include, but are not limited to, NS-386,nimesulide, flosulide, celecoxib, rofecoxib, COX-189, etoracoxib,Bextra, Dynastat, Arcoxia, SC-57666, DuP 697, SC-58125, SC-58635, andthe like. Suitable COX-2 inhibitors are in U.S. Pat. Nos. 5,344,991,5,380,738, 5,393,790, 5,409,944, 5,434,178, 5,436,265, 5,466,823,5,474,995, 5,510,368, 5,536,752, 5,550,142, 5,552,422, 5,604,253,5,604,260, and 5,639,780 and in WO 94/03387, WO 94/15723, WO 94/20480,WO 94126731, WO 94/27980, WO 95/00501, WO 95/15316, WO 96/03387, WO96/03388, WO 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO97/14691, WO 97/16435, WO 01/45703 and WO 01/87343; the disclosures ofwhich are incorporated herein by reference in their entirety.

Suitable NSAIDs, include, but are not limited to, acetaminophen,aspirin, diclofenac, ibuprofen, ketoprofen, naproxen, indomethacin,including but not limited to prodrugs thereof, and the like. SuitableNSAIDs are described more fully in the literature, such as in Goodmanand Gilman, The Pharmacological Basis of Therapeutics (9th Edition),McGraw-Hill, 1995, Pgs. 617–657; the Merck Index on CD-ROM, 13^(th)Edition; and in U.S. Pat. Nos. 6,057,347 and 6,297,260 assigned toNitroMed Inc., the disclosures of which are incorporated herein byreference in their entirety.

Suitable H₂ receptor anatgonists, include, but are not limited to,cimetidine, roxatidine, rantidine and the like. Suitable H₂ receptorantagonists are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 901–915; the Merck Index on CD-ROM,13^(th) Edition; and in WO 00/28988 assigned to NitroMed Inc., thedisclosures of which are incorporated herein by reference in theirentirety.

Suitable antineoplastic agents, include but are not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine,anaxirone, aclarubicin and the like. Suitable antineoplastic agents arealso described in U.S. Pat. No. 6,025,353 and WO 00/38730, thedisclosures of which are incorporated herein by reference in theirentirety.

Suitable antiplatelet agents, include but are not limited to, aspirin,ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIa receptorantagonists, and the like. Suitable antineoplastic agents are alsodescribed in WO 99/45913, the disclosure of which is incorporated hereinby reference in its entirety. In a preferred embodiment of theinvention, the antiplatelet agent is aspirin, more preferably, low-doseaspirin (i.e. 75 mg–100 mg/day).

Suitable thrombin inhibitors, include but are not limited to,N′-((1-(aminoiminoinethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylpropinyl)-L-prolineamide),3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylene-carboxamidomethylpyridinyl)-2-pyrazinone,3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone,and the like. Suitable thrombin inhibitors are also described in WO00/18352, the disclosure of which is incorporated herein by reference inits entirety.

Suitable thromboxane inhibitors, include but are not limited tothromboxane synthase inhibitors, thromboxane receptor antagonists, andthe like. Suitable thromboxane inhibitors, are also described in WO01/87343, the disclosure of which is incorporated herein by reference inits entirety.

Suitable decongestants include, but are not limited to, phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, levo-desoxyephedrine, andthe like.

Suitable antitussives include, but are not limited to, codeine,hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.

Suitable proton pump inhibitors, include, but are not limited to,omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, andthe like. Suitable proton pump inhibitors are described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901–915; theMerck Index on CD-ROM, 13 ^(th) Edition; and in WO 00/50037 assigned toNitroMed Inc., the disclosures of which are incorporated herein byreference in their entirety.

The compounds and compositions of the invention, may also be used incombination therapies with opioids and other analgesics, including, butnot limited to, narcotic analgesics, Mu receptor antagonists, Kappareceptor antagonists, non-narcotic (i.e. non-addictive) analgesics,monoamine uptake inhibitors, adenosine regulating agents, cannabinoidderivatives, neurokinin 1 receptor antagonists, Substance P antagonists,neurokinin-1 receptor antagonists, sodium channel blockers,N-methyl-D-aspartate receptor antagonists, and mixtures of two or morethereof. Preferred combination therapies would be with morphine,meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine,meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+)enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-116.08,E-2078, ICI-204448, acetoiinophein (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631,Tramadol ((−) enantiomer), GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, and mixturesof two or more thereof.

The compounds and compositions of the invention can also be used incombination with inducible nitric oxide synthase (iNOS) inhibitors.Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos. 5,132,453 and5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of eachof which are incorporated by reference herein in their entirety.

The invention is also based on the discovery that the administration ofa therapeutically effective amount of the compounds and compositionsdescribed herein is effective for treating inflammation, pain (bothchronic and acute), and fever, such as, for example, analgesic in thetreatment of pain, including, but not limited to headaches, migraines,postoperative pain, dental pain, muscular pain, and pain resulting fromcancer; as an antipyretic for the treatment of fever, including but notlimited to, rheumatic fever, symptoms associated with influenza or otherviral infections, common cold, low back and neck pain, dysmenorrhea,headache, toothache, sprains, strains, myositis, neuralgia, synovitis,menstrual cramps; arthritis, including but not limited to rheumatoidarthritis, degenerative joint disease (osteoarthritis),spondyloarthropathies, gouty arthritis, systemic lupus erythematosus andjuvenile arthritis. For example, the patient can be administered atherapeutically effective amount of least one nitrosated NSAID. Inanother embodiment, the patient can be administered a therapeuticallyeffective amount of at least one nitrosated NSAID, and at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. In yet another embodiment, the patient can beadministered a therapeutically effective amount of at least onenitrosated NSAID, and, at least one therapeutic agent, including but notlimited to, steroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

Another embodiment of the invention provides methods for treatinggastrointestinal disorders by administering to the patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. Such gastrointestinal disorders refer toany disease or disorder of the upper gastrointestinal tract (e.g.,esophagus, the stomach, the duodenum, jejunum) including, for example,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, constipation, ulcerative colitis, peptic ulcers, stressulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterialinfections (including, for example, a Helicobacter Pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. Forexample, the patient can be administered a therapeutically effectiveamount of least one nitrosated NSAID of the invention. In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one nitrosated NSAID, and at least one compound thatdonates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. In yet another embodiment, the patient can be administered atherapeutically effective amount of at least one nitrosated NSAID, and,at least one therapeutic agent, including but not limited to, steroids,cyclooxygenase-2 (COX-2) inhibitors, nonsteroidal antiinflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,5-HT agonists, HMG CoA inhibitors, H₂ antagonists, antineoplasticagents, antiplatelet agents, thrombin inhibitors, thromboxaneinhibitors, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. The compounds can be administered separately or in the form ofa composition.

Yet another embodiment of the invention provides methods facilitatingwound healing (such as, for example, ulcer healing bone healingincluding osteoporosis) by administering to the patient in need thereofa therapeutically effective amount of the compounds and/or compositionsdescribed herein. Wound refers to, and includes, any lesion that ischaracterized by loss of tissue, and, includes, but is not limited to,ulcers, cuts, burns, bone fractures, orthopedic procedure, woundinfliction, and the like. Ulcers refers to lesions of the uppergastrointestinal tract lining that are characterized by loss of tissue,and, include, but are not limited to, gastric ulcers, duodenal ulcers,gastritis, and the like. For example, the patient can be administered atherapeutically effective amount of least one nitrosated NSAID of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one nitrosated NSAID and atleast one compound that donates, transfers or releases nitric oxide, orelevates levels of endogenous EDRF or nitric oxide, or is a substratefor nitric oxide synthase. In yet another embodiment, the patient can beadministered a therapeutically effective amount of at least onenitrosated NSAID and at least one therapeutic agent, including but notlimited to, steroids, cyclooxygenase-2 (COX-2) inhibitors, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

Another embodiment of the invention provides methods for decreasingand/or reversing gastrointestinal, renal, respiratory and other toxicity(such as, for example, kidney toxicity) resulting from the use of drugs,such as, nonsteroidal anti-inflammatory drugs and/or cyclooxygenase-2(COX-2) inhibitors by administering to a patient in need thereof atherapeutically effective amount of the compounds and/or compositionsdescribed herein. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated NSAID of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one nitrosated NSAID and atleast one nitric oxide donor. In yet another embodiment, the patient canbe administered a therapeutically effective amount of at least onenitrosated NSAID and at least one therapeutic agent, and, optionally, atleast one nitric oxide donor. The compounds can be administeredseparately or in the form of a composition.

Another embodiment of the invention provides for treating inflammatorydisease states and disorders by administering to a patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. Such inflammatory disease states and/ordisorders include, for example, cardiovascular disorder, reperfusioninjury to an ischemic organ, angiogenisis, arthritis, including but notlimited to rheumatoid arthritis, degenerative joint disease(osteoarthritis), spondyloarthropathies, gouty arthritis, systemic lupuserythematosus and juvenile arthritis; asthma, bronchitis, prematurelabor, tendinitis, bursitis; autoimmune diseases, immunologicaldisorders; skin-related conditions, such as, for example, psoriasis,eczema, surface wounds, burns and dermatitis; post-operativeinflammation including from ophthalmic surgery, such as, for example,cataract surgery and refractive surgery, and the like; neoplasia, suchas, for example, brain cancer, bone cancer, epithelial cell-derivedneoplasia (epithelial carcinoma), such as, for example, basal cellcarcinoma, adenocarcinoma, gastrointestinal cancer, such as, forexample, lip cancer, mouth cancer, esophageal cancer, small bowel cancerand stomach cancer, colon cancer, liver cancer, bladder cancer, pancreascancer, ovary cancer, cervical cancer, lung cancer, breast cancer andskin cancer, such as squamus cell and basal cell cancers, prostatecancer, renal cell carcinoma, and other known cancers that effectepithelial cells throughout the body, benign and cancerous tumors,growths, polyps, adenomatous polyps, including, but not limited to,familial adenomatous polyposis, fibrosis resulting from radiationtherapy, and the like; inflammatory processes in diseases, such as, forexample, vascular diseases, periarteritis nodosa, thyroiditis, aplasticanemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes,neuromuscular junction disease including myasthenia gravis, white matterdisease including multiple sclerosis, sarcoidosis, nephrotic syndrome,Behcet's syndrome, polymyositis, gingivitis, nephritis,hypersensitivity, swelling occurring after injury, myocardial ischemia,and the like; pulmonary inflammation, such as, for example, thoseassociated with viral infections and cystic fibrosis, and the like;central nervous system disorders, such as, for example, corticaldementia including Alzheimer's disease, vascular dementia, multi-infarctdementia, pre-senile dementia, alcoholic dementia, senile dementia,memory loss and central nervous system damage resulting from stroke,ischemia and trauma, and the like; allergic rhinitis, respiratorydistress syndrome, endotoxin shock syndrome, inflammations and/ormicrobial infections including, for example, inflammations and/orinfections of the eyes, ears, nose, throat, and/or skin;bacterial-induced inflammation, such as, for example, Chlamydia-inducedinflammation; viral induced inflammation, urinary and/or urologicaldisorders, such as, for example, incontinence and the like; endothelialdysfunctions, such as, for example, diseases accompanying thesedysfunctions, endothelial damage from hypercholesterolemia, endothelialdamage from hypoxia, endothelial damage from mechanical and chemicalnoxae, especially during and after drug, and mechanical reopening ofstenosed vessels, for example, following percutaneous transluminalangiography (PTA) and percuntaneous transluminal coronary angiography(PTCA), endothelial damage in postinfarction phase, endothelium-mediatedreocculusion following bypass surgery, blood supply distrubances inperipheral arteries, and the like; sexual dysfunction; tissuedeterioration, such as, for example, for organ transplant rejection, andthe like; disorders treated by the inhibition and/or prevention ofactivation, adhesion and infiltration of neutrophils at the site ofinflammation; and disorders treated by the inhibition and/or preventionof platelet aggregation. The compounds and compositions of the inventioncan also be used as a pre-anesthetic medication in emergency operationsto reduce the danger of aspiration of acidic gastric contents. Forexample, the patient can be administered a therapeutically effectiveamount of least one nitrosated NSAID. In another embodiment, the patientcan be administered a therapeutically effective amount of at least onenitrosated NSAID and at least one compound that donates, transfers orreleases nitric oxide, or elevates levels of endogenous EDRF or nitricoxide, or is a substrate for nitric oxide synthase. In yet anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one nitrosated NSAID, and, at least one therapeuticagent, including but not limited to, steroids, cyclooxygenase-2 (COX-2)inhibitors, nonsteroidal antiinflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,HMG CoA inhibitors, H₂ antagonists, antineoplastic agents, antiplateletagents, thrombin inhibitors, thromboxane inhibitors, decongestants,diuretics, sedating or non-sedating anti-histamines, inducible nitricoxide synthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and,optionally, at least one compound that donates, transfers or releasesnitric oxide; or elevates levels of endogenous EDRF or nitric oxide, oris a substrate for nitric oxide synthase. The compounds can beadministered separately or in the form of a composition.

Another embodiment of the invention provides methods for treating and/orpreventing ophthalmic diseases and disorders by administering to apatient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. For example, the patientcan be administered a therapeutically effective amount of at least onenitrosated NSAID. In another embodiment, the patient can be administereda therapeutically effective amount of at least one nitrosated NSAID andat least one nitric oxide donor. In yet another embodiment, the patientcan be administered a therapeutically effective amount of at least onenitrosated NSAID and at least one therapeutic agent, and, optionally, atleast one nitric oxide donor. The compounds can be administeredseparately or in the form of a composition. Such ophthalmic diseases anddisorders include, for example, retinitis; retinopathies, uveitis,ocular photophobia, acute injury to the eye tissue, glaucoma,inflammation of the eye and elevation of intraocular pressure and thelike.

When administered separately, the nitrosated NSAID can be administeredabout the same time as part of the overall treatment regimen i.e., as acombination therapy. “About the same time” includes administering thenitrosated NSAID, simultaneously, sequentially, at the same time, atdifferent times on the same day, or on different days, as long as theyare administered as part of an overall treatment regimen, i.e.,combination therapy or a therapeutic cocktail.

When administered in vivo, the compounds and compositions of theinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. When the compoundsand compositions of the invention are administered as a combination ofat least one nitrosated NSAID and/or at least one nitric oxide donorand/or therapeutic agent, they can also be used in combination with oneor more additional compounds which are known to be effective against thespecific disease state targeted for treatment. The nitric oxide donors,therapeutic agents and/or—other additional compounds can be administeredsimultaneously with, subsequently to, or prior to administration of thenitrosated NSAID.

The compounds and compositions of the invention can be administered byany available and effective delivery system including, but not limitedto, orally, bucally, parenterally, by inhalation spray, by topicalapplication, by injection, transdermally, or rectally (e.g., by the useof suppositories) in dosage unit formulations containing conventionalnontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles,as desired. Parenteral includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of theinvention and vegetable oil. Hard, gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention, such as for treating pediatric fever andthe like, can be prepared by mixing the compounds or compositions with asuitable nonirritating excipient such as cocoa butter and polyethyleneglycols which are solid at room temperature but liquid at rectaltemperature, such that they will melt in the rectum and release thedrug.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, salt solutions,alcohol, vegetable oils, semi-solid fats, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, surfactants, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation, or powder. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides. Oral formulations can include standard carriers suchas pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, and thelike.

Various delivery systems are known and can be used to administer thecompounds or compositions of the invention, including, for example,encapsulation in liposomes, microbubbles, emulsions, microparticles,microcapsules and the like. The required dosage can be administered as asingle unit or in a sustained release form.

The bioavailabilty of the compositions can be enhanced by micronizationof the formulations using conventional techniques such as grinding,milling, spray drying and the like in the presence of suitableexcipients or agents such as, for example, phospholipids and/or at leastone or more surfactants, and, optionally cosufactants, as disclosed in,for example, WO 01/66088 and WO 03/022249, the disclosures of each ofwhich are incorporated by reference herein in their entirety.

Suitable natural or synthetic phospholipids include, but are not limitedto, non-ionic surfactants containing a hydrogenated or non-hydrogenatedphosphatidyl choline, a diglyceride linked to a choline wster ofphosphoric acid, such as for example, lecithin, obtained from any sourceincluding soya or eggs, or a mixture thereof.

Suitable sufactants include, but are not limited to, surface-activeamphiphilic compounds, such as, for example, block co-polymers;non-ionic surfactants, such as, poloxamers, such as, for example,Poloxamer 407, Poloxamer 401, Poloxamer 338, Poloxamer 331, Poloxamer231, and the like; tetrafunctional polyoxyethylene polyoxypropyleneblock copolymers of ethylene diamane, such as, for example, Poloxamine908, Poloxamine 1307, and the like; polyoxyethylene polyoxybutyleneblock copolymers, such as, for example Polyglycol BM45, and the like.

The preferred methods of administration of the NSAIDs and compositionsfor the treatment of gastrointestinal disorders are orally, bucally orby inhalation. The preferred methods of administration for the treatmentof inflammation and microbial infections are orally, bucally, topically,transdermally or by inhalation.

The compounds and compositions of the invention can be formulated aspharmaceutically acceptable salt forms. Pharmaceutically acceptablesalts include, for example, alkali metal salts and addition salts offree acids or free bases. The nature of the salt is not critical,provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic,galactaric and galacturonic acid and the like. Suitablepharmaceutically-acceptable base addition salts include, but are notlimited to, metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromprimary, secondary and tertiary amines, cyclic amines,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine and thelike. All of these salts may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound.

While individual needs may vary, determination of optimal ranges foreffective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

The amount of a given nitrosated NSAID which will be effective in thetreatment of a particular disorder or condition will depend on thenature of the disorder or condition, and can be determined by standardclinical techniques, including reference to Goodman and Gilman, supra;The Physician's Desk Reference, Medical Economics Company, Inc.,Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis,Mo., 1993. The precise dose to be used in the formulation will alsodepend on the route of administration, and the seriousness of thedisease or disorder, and should be decided by the physician and thepatient's circumstances.

The amount of nitric oxide donor in a pharmaceutical composition can bein amounts of about 0.1 to about 10 times the molar equivalent of theNSAID. The usual daily doses of NSAIDs are about 3 to about 40 mg/kg ofbody weight and the doses of nitric oxide donors in the pharmaceuticalcomposition can be in amounts of about 1 to about 500 mg/kg of bodyweight daily, preferably about 1 to about 50 mg/kg of body weight daily.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems and are in the same ranges orless than as described for the commercially available compounds in thePhysician's Desk Reference, supra.

The amount of nitric oxide donor in a pharmaceutical composition can bein amounts of about 0.1 to about 10 times the molar equivalent of theNSAID. The usual daily doses of NSAIDs are about 3 to about 40 mg/kg ofbody weight and the doses of nitric oxide donors in the pharmaceuticalcomposition can be in amounts of about 1 to about 500 mg/kg of bodyweight daily, preferably about 1 to about 50 mg/kg of body weight daily.The compounds may be administered on a regimen of up to 6 times per day,preferably 1 to 4 times per day, and most preferably twice per day.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems and are in the same ranges orless than as described for the commercially available compounds in thePhysician's Desk Reference, supra.

The invention also provides pharmaceutical kits comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the invention,including, at least, one or more of the novel nitrosated NSAID, and oneor more of the NO donors described herein. Associated with such kits canbe additional therapeutic agents or compositions (eg., steroids, COX 2inhibitors, nonsteroidal antiinflammatory compounds (NSAID)5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists and leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, IMG-CoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and the like), devices for administering the compositions,and notices in the form prescribed by a governmental agency regulatingthe manufacture, use or sale of pharmaceuticals or biological productswhich reflects approval by the agency of manufacture, use or sale forhumans.

EXAMPLES

The following non-limiting examples further describe and enable one ofordinary skill in the art to make and use the present invention. In eachof the examples, flash chromatography was performed on 40 micron silicagel (Baker).

Example 12-(2-(Nitrooxy)ethylthio)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate1a. 2-(2-Hydroxyethylthio)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,15.0 g, 65 mmol), 2,2′-thiodiethanol (40 g, 325 mmol) andN,N-dimethylaminopyridine (DMAP, 1.59 g, 13 mmol) in dichloromethane(400 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 14.98 g, 78 mmol) as asolid, in portions. After stirring for 3 hours at room temperature, TLCanalysis indicated the reaction was complete. The reaction mixture waspartitioned between CH₂Cl₂ and water, and the water layer was washedwith more CH₂Cl₂. The combined organic layer was washed with water, 0.1N HCl, water, brine, and dried over magnesium sulfate. The solution wasconcentrated under vacuum, and the residue was purified via columnchromatography, 5% ethyl acetate/dichloromethane. The appropriatefractions were combined, and the solvent evaporated. Trituration of theresidue with ether/hexane gave the title compound as a white solid(17.72 g, 81% yield). Mp 58–61° C. ¹H NMR (300 MHz, CDCl₃) δ 7.70 (d,J=8.6 Hz, 2H), 7.67 (d, J=0.9 Hz, 1H), 7.40 (dd, J=1.7, 8.5 Hz, 1H),7.14(dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 4.24 (t, J=6.7 Hz,2H), 3.86 (q, J=7.2 Hz, 1H), 3.60 (app q, J=6.0 Hz, 2H), 2.69 (t, J=6.6Hz, 2H), 2.61 (t, J=5.9 Hz, 2H), 2.00 (t, J=6.2 Hz 1H), 1.59 (d, J=7.2Hz, 3H). Mass spectrum (API-TIS) m/z 352 (MNH₄ ⁺); Anal. calcd. forC₁₈H₂₂O₄S: C, 64.65; H, 6.63, S, 9.59. Found: C, 64.62; H 6.59; S, 9.47.

1b.2-(2-(Nitrooxy)ethylthio)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To acetic anhydride (3.73 mL, 40.3 mmol) at 0° C. was added fumingnitric acid (90%, 1.25 mL, 26.9 mmol) with stirring. After the additionwas complete, the reaction mixture was stirred at room temperature for40 minutes, then added drop-wise to a solution of the product of Example1a (6.0 g, 17.9 mmol) in ethyl acetate at 0° C. The reaction mixture wasstirred at 0° C. for 3 hours, and then poured into a pre-cooled (0° C.)mixture of 75 mL of ethyl acetate and 100 mL of sodium bicarbonate. Themixture was stirred cold for 20 minutes, and then warmed to roomtemperature for 1 hour. The reaction mixture was partitioned betweenethyl acetate and water, washed with sodium bicarbonate, water, andbrine, and dried over sodium sulfate. The solvent was evaporated and theresidue purified by column chromatography on silica, eluting with 25%ethyl acetate/hexane, to give the title compound as an oil, which slowlysolidified (2.11 g, 5.56 mmol, 31% yield). Mp 33–37° C. ¹H NMR (300 MHz,CDCl₃) δ 7.72 (s, 1H), 7.69 (s, 1H), 7.66 (d, J=1.3 Hz, 1H), 7.39 (dd,J=1.8, 8.8 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.5 Hz,1H), 4.37 (d, J=6.9 Hz, 2H), 4.26 (m, 22H), 3.92 (s, 3H), 3.86 (q, J=7.2Hz, 1H), 2.72 (dt, J=1.5, 6.5 Hz, 2H), 2.63 (m, 2H), 1.59 (d, J=7.2 Hz,3H). Mass spectrum (API-TIS) m/z 380 (MH⁺), 397 (M+18⁺). Anal. calcd.for C₁₈H₂₁NO₆S: C, 56.98; H, 5.58; N, 3.69; S, 8.45. Found: C, 57.38; H,5.56; N, 3.29; S, 8.45.

Example 22-((2-(Nitrooxy)ethyl)sulfonyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate2a.2-((2-Hydroxyethyl)sulfonyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

The product of Example 1a (4.55 g, 13.60 mmol) was dissolved inmethanol/water (3:1), 160 mL and cooled to 0° C. OXONE® (17.56 g, 28.6mmol) was added in portions, as a solid. The resulting mixture wasstirred at 0° C. for 1.5 hours, and filtered then though Celite. Thebulk of the solvent was evaporated, and the residue was partitionedbetween CH₂Cl₂ and water. The organic layer was dried over magnesiumsulfate, and evaporated to give the title compound as an off-white solid(4.48 g, 90% yield). Mp 81–84° C. ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d,J=7.7 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.65 (d, J=1.2 Hz, 1H), 7.36 (dd,J=1.8, 8.5 Hz, 1H), 7.17 (dd, J=2.5 Hz, 1H), 7.12 (d, J=2.5 Hz, 1H),4.57 (m, 1H), 4.46 (m, 1H), 3.92 (s, 3H), 3.87 (q, J=7.2 Hz, 1H), 3.52(m, 2H), 3.27 (app t, J=5.5 Hz, 2H), 2.64 (m, 1H), 2.58 (m, 1H), 1.87(t, J=6.1 Hz, 1H), 1.60 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z367 (MH⁺), 384 (MNH₄ ⁺). Anal. calcd. for C₁₈H₂₂O₆S: C, 59.00; H, 6.05;S. 8.75. Found: C, 59.08; H, 5.89; S, 8.75.

2b.2-((2-(Nitrooxy)ethyl)sulfonyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

The title compound was prepared from the product of Example 2a (4.48 g,12.2 mmol) and fuming nitric acid (90%, 1.43 mL, 30.6 mmol) in aceticanhydride (4.54 mL, 49 mmol) following the procedure for Example 1b.After purification by column chromatography on silica, eluting with 50%ethyl acetate/hexane and trituration with ether/hexane, the titlecompound was obtained as white needles (3.348 g, 66% yield). Mp 83–85°C. ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.9 Hz,1H), 7.64 (d, J=1.3 Hz, 1H), 7.34 (dd, J=1.8, 8.4 Hz, 1H), 7.18 (dd,J=2.5, 8.9 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 4.59 (m, 1H), 4.44 (m, 1H),4.15 (m, 2H), 3.93 (s, 3H), 3.88 (q, 1H), 3.22 (m, 2H), 2.64 (m, 1H),2.52 (m, J=7.2 Hz, 1H), 1.62 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS)m/z 412 (MH⁺), 429 (M+18⁺). Anal. calcd. for C₁₈H₂₁NO₈S: C, 52.55; H,5.14; N, 3.40; S, 7.79. Found: C, 52.50; H, 4.94; N, 3.27; S, 7.79.

Example 32-((2-(Nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate 3a.2-((2-Hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoateand2-((2-(Nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To acetic anhydride (9.1 mL, 98.1 mmol) at 0° C. was added fuming nitricacid (90%, 2.86 mL, 61.3 mmol) with stirring. After addition wascomplete, the mixture was stirred at 0° C. for 5 minutes, then addeddrop-wise to a solution of the product of Example 1a (4.10 g, 12.3 mmol)in ethyl acetate (20 mL) at 0° C. The reaction mixture was stirred at 0°C. for 10 minutes, then poured into a pre-cooled (0° C.) mixture of 25mL of ethyl acetate and 50 mL of sodium bicarbonate. The mixture wasstirred cold for 20 minutes, and then warmed to room temperature for 1hour. The reaction mixture was partitioned between ethyl acetate andwater, washed with sodium bicarbonate, water, and brine, and dried oversodium sulfate. The solvent was evaporated and the residue was purifiedby column chromatography on silica, eluting with methanol/ethyl acetate(gradient, 0% to 20%), gave 2-((2-nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate as a pale yellow solid (1.07 g,22% yield) and2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoateas a white solid.2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate(1.87 g, 44% yield). Mp 74–86° C. ¹H NM (300 MHz, CDCl₃) δ 7.70 (d,J=8.6 Hz, 2H), 7.65 (d, J=1.0 Hz, 1H), 7.37 (dt, J 1.9, 8.5 Hz, 1H),7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 4.52 (m, 2H), 3.91(s, 3H), 3.87 (q, J=7.2 Hz, 1H), 2.97 (m, 2H), 2.84 (br.s, 1H), 2.62 (m,2H), 1.59 (d, J=7.2 Hz, 3H) Mass spectrum (API-TIS) m/z 351 (MH⁺).

2-((2-(nitrooxy)ethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate.Mp 72–88° C. ¹H NMR (300 MHz, CDCl₃) δ 7.72 (d, J=8.4 Hz, 1H), 7.70 (d,J=8.9 Hz, 1H), 7.64 (br s, 1H), 7.35 (dt, J=2.1, 8.5 Hz, 1H), 7.16 (dd,J=2.5, 8.9 Hz, 1H), 7.11 (br s, 1H), 4.54–4.29 (m, 4H), 3.91 (s, 3H),3.86 (q, J=7.2 Hz, 1H), 3.01–2.83 (m, 2H), 2.64–2.46 (m, 2H), 1.60 (d,J=7.2 Hz, 3H). Mass spectrum (API-ITS) m/z 396 (M⁺), 413 (M+18⁺).

Example 4 2-((2-(Nitrooxy)ethyl)4-nitrophenyl)amino)ethyl2-(6-methoxy-2-naphthyl)propanoate 4a.2-((Hydroxyethyl)(4-nitrophenyl)amino)ethan-1-ol

A mixture of 4-fluoronitrobenzene (5 g, 35 mmol) and diethanolamine (7.5g, 71 mmol) was heated to 130° C. without solvent for 4 hours. The crudereaction mixture after chromatography on silica gel (gravity,methanol:dichloromethane 1:19 then 1:9) gave the title compound (6.7 g,85% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.98 (d, 2H), 6.78 (d, 2H), 4.83(t, 2H), 3.50–3.65 (m, 8H). ¹³C NMR (75, DMSO-d₆) δ 154.36, 136.16,126.77, 111.66, 58.89, 54.17. Mass spectrum m/z 227 (MH⁺). Anal. calcd.for C₁₀H₁₄N₂O₄ C, 53.09; H, 6.24; N, 12.38. Found C, 53.09, H, 6.32, N,12.34.

4b.2-((2-Hydroxyethyl)(4-nitrophenyl)amino)ethyl2-(6-methoxy-2-naphthyl)propanoate

A solution of the product of Example 4b (6.7 g, 29.6 mmol),N,N-dimethylaminopyridine (DMAP, 0.24 g, 2 mmol), and(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 2.27 g, 9.9mmol) in dichloromethane (90 ml) with enough DMF to cause dissolution,was treated with 1-ethyl-3(3-dimethylamino)-1-propylcarbodiimide (2.35g, 12.3 mmol). The reaction mixture was stirred at room temperature for4 hours, diluted with CH₂Cl₂, washed with water (8×), HCl (2N), brine,dried with sodium sulfate, filtered and the organic layer evaporated.The residue was chromatographed on silica gel (gravity,methanol:dichloromethane, 1:24) to give the title compound (2.7 g, 64%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.87–7.95 (m, 2H), 7.60–7.69 (m, 2H),7.56 (s, 1H), 7.26–7.32 (s, 1H), 7.11–7.19 (m, 1H), 7.08 (br s, 1H),6.46–6.54 (m, 2H), 4.22–4.45 (m, 2H), 3.89 (s, 3H), 3.77 (q, j=6.0 Hz,1H), 3.55–3.67 (m, 4H), 3.27–3.39 (m, 2H), 1.90 (br s, 1H), 1.51 (d,J=6.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.63, 157.75, 152.66, 137.28,135.06, 133.67, 129.07, 128.76, 127.21, 125.96, 125.89, 119.16, 110.59,105.53, 61.61, 59.57, 55.28, 53.19, 50.07, 45.36, 18.30. Mass spectrumm/z 439 (MH⁺).

4c. 2-((2-(Nitrooxy)ethyl)4-nitrophenyl)amino)ethyl2-(6-methoxy-2-naphthyl)propanoate

Acetic anhydride (5 mL) was cooled to <10° C. (internal temperature) andfuming nitric acid (90%, 1 mL) was added keeping the same temperature. Asolution of the product of Example 4b (2.4 g, 5.5 mmol) in ethyl acetate(30 ml) was added drop-wise at the same temperature. After the additionwas complete, the reaction mixture was stirred in the ice bath for 1hour, poured carefully into excess sodium bicarbonate solution andextracted with ethyl acetate. The combined organic layers were driedwith sodium sulphate, filtered, evaporated and the residuechromatographed on silica gel (gravity, ethyl acetate:hexane 1:1) togive the title compound (1.7 g, 64% yield). ¹HNMR (300 MHz, CDCl₃) δ7.98 (dd, J=11.0 and 3.4 Hz, 2H), 7.65 (dd, J=8.4 and 2.4 Hz, 2H), 7.53(s, 1H), 7.28 (dd, J=8.5 and 1.8 Hz, 1H), 7.16 (dd, J=8.9 and 2.5 Hz,1H), 7.10 (d, J=2.3 Hz, 1H), 6.45–6.51 (m, 2H), 4.08–4.48 (m, 4H), 3.93(s, 3H), 3.80 (q, Jf=7.1 Hz, 1H), 3.59 (q, J=5.9 Hz, 2H), 3.20–3.43 (m,2H), 1.54 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.34, 157.84,151.47, 138.11, 135.13, 133.70, 129.03, 128.77, 127.28, 126.10, 125.91,119.28, 110.57, 105.53, 68.93, 61.30, 55.31, 49.82, 47.62, 45.35, 18.19.Mass spectrum m/z 484 (MH⁺).

Example 5(2R)-2,3-Bis(nitrooxy)propyl(2S)-2(6-methoxy(2-naphthyl)propanoate 5a.1-(((4S)-2,2-Dimethyl(1,3-dioxolan-4-yl))methoxy)-2,2-dimethyl-1,1-diphenyl-1-silapropane

To a solution of ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol (9 g,68.6 mmol) in anhydrous dichloromethane (40 mL) were added triethylamine(11.2 mL), tert-butylchlorodiphenylsilane (19.8 g, 372 mmol), andN,N-dimethylaminopyridine (DMAP, 418 mg, 3.4 mmol) at room temperatureunder a nitrogen atmosphere. The reaction mixture was stirred at roomtemperature overnight. It was then diluted with additionaldichloromethane and the reaction mixture was washed with water, brine,dried over sodium sulfate, filtered and evaporated to give the titlecompound (27 g) which was used in the next step without furtherpurification.

5b. (2S)-3-(2,2-Dimethyl-1,1-diphenyl-1-silapropoxy)propane-1,2-diol

The product of Example 5a (12.3 g, 33.2 mmol) was dissolved in 70%aqueous acetic acid (10 mL) and the resulting solution was stirred at60° C. for 2 hours. The reaction mixture was then cooled to roomtemperatures and sodium carbonate was added to neutralize the acid. Thereaction mixture was then extracted with ethyl acetate, the combinedorganic extracts were washed with water, brine, dried over sodiumsulfate, filtered, and evaporated to give the title compound (8.3 g) asa colorless viscous oil which was used as such in the next step.

5c.((1S)-1-((2,2-Dimethyl-1,1-diphenyl-1-silapropoxy)methyl)-2-(nitrooxy)ethyl)nitrooxy

The product of Example 5b (9.82 g, 38.5 mmol) was dissolved in ethylacetate (200 mL) and the resulting solution was cooled to 0° C. Amixture of acetic acid (20 mL) and fuming nitric acid (90%, 3.8 mL) wasthen added followed by acetic anhydride (20 mL). The resulting mixturewas stirred at room temperature overnight. The reaction mixture was thendiluted with ethyl acetate, washed with saturated aqueous sodiumbicarbonate, water, brine, dried over sodium sulfate, filtered, and thefiltrate was concentrated in vacuo to give the title compound (10.6 g,80% yield) as a yellow oil which was used without further purification.

5d. (2R)-2,3-Bis(nitrooxy)propan-1-ol

The product of Example 5c (8.67 g, 25.1 mmol) was dissolved inacetonitrile (200 mL) and hydrofluoric acid (48% solution in water, 100mL) was added. The reaction mixture was stirred at room temperatureovernight. A saturated aqueous sodium bicarbonate was added toneutralize the acidic solution to pH 7.0 and the mixture was extractedwith ethyl acetate. The combined extracts were washed with saturatedaqueous sodium bicarbonate, water, brine, dried over sodium sulfate,filtered, and the filtrate was concentrated in vacuo to give the crudeproduct that was purified by column chromatography over silica gel,eluting with 5% ethyl acetate in hexane to give the title compound (1.38g, 23% yield) as a colorless oil.

5e. (2R)-2,3-Bis(nitrooxy)propyl(2S)-2(6-methoxy(2-naphthyl)propanoate

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,1.05 g, 5 mmol) and the product of Example 5d (0.91 g, 5 mmol) inanhydrous dichloromethane (25 mL) were added1-ethyl-3-(3-dimethylaminopropyl) carbamide hydrochloride (EDAC) (0.955g, 5 mmol) and N,N-dimethylaminopyridine (DMAP, 0.61 g, 5 mmol) at 0° C.under nitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 5 hours. The solvent was evaporated under vacuo and theresidue was extracted with ethyl acetate, washed with water, brine,dried over sodium sulfate, filtered, and the combined organic extractswere evaporated. The product was purified by column chromatography onsilica gel eluting with EtOAc:hexane (20:80) to give the title compound(1.5 g, 82% yield) as a white solid, mp 0.54–58° C. ¹H NMR (300 MHz,CDCl₃) δ 7.72 (dd, J=9 and 2 Hz, 2H), 7.65 (s, 1H), 7.36 (dd, J=8.5 and1.8 Hz, 1H), 7.16 (dd, J=8.8 and 2.5 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H),5.33 (m, 1H), 4.55,(dd, J=12.9 and 3.6 Hz, 1H), 4.46 (dd, J=12.5 and 4.2Hz, 1H), 4.32 (dd, J=12.8 and 6.5 Hz, 1H), 4.21 (dd, J=12.5 and 5.5 Hz,1H), 3.91 (s, 3H), 3.89 (q, J=7.1 Hz, 1H), 1.6 (d, J=7.1 Hz, 3 H); ¹³CNMR (75 MHz, CDCl₃) δ 173.8, 157.7, 134.6, 133.8, 129.2, 128.8, 127.3,125.9, 125.8, 119.2, 105.6, 76.2, 68.4, 60.4, 55.2, 45.1, 18.0; LRMS(APIMS) m/z 395 (MH⁺).

Example 6(2R)-7-(Nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,1 g, 4.43 mmol) and (2S)-7-(nitrooxy)-4,8-dioxabicyclo(3.3.0) octan-2-ol(isosorbide 5-mononitrate, 1 g, 5.21 mmol) in anhydrous dichloromethane(25 mL) were added 1-(3(dimethylamino)propyl)-3-ethylcarbodiimidehydrochloride (EDAC, 1.17 g, 1.4 eq) and a catalytic amount ofN,N-dimethylaminopyridine (DMAP) at room temperature under nitrogenatmosphere. The reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with CH₂Cl₂ and washed H₂O,brine, dried over sodium sulfate, filtered, and the organic extractswere evaporated. The product was purified by column chromatography onsilica gel eluting with EtOAc:hexane (3:7 to 1:1) to give the titlecompound (1.71 g, 97.6% yield) as a white crystalline solid. Mp 112–113°C. ¹H NMR (300 MHz, CDCl₃) δ 7.67 (m, 3H), 7.37 (m, 1H), 7.14 (m, 2H),5.26 (m, 2H), 4.78 (t, J=5.2 Hz, 1H), 4.21 (d, J=4.9 Hz, 1H), 4.02–3.77(m, 5H), 3.92 (s, 3H), 1.56 (d, 3H, J=7.1 Hz); LRMS (APIMS) m/z 404(MH⁺).

Example 7 Phosphonomethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate3-(nitrooxy)propylamine nitricacid salt 7a.(Diethoxycarbonyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproken,16.55 g, 71.9 mmol), diethyl (hydroxymethy)phosphonate (12.68 g, 75.4mmol) and N,N-dimethylaminopyridine (DMAP, 20 mg) in dichloromethane(200 ml) was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC,14.45 g, 75.4 mmol) and stirred at room temperature overnight. Thereaction mixture was washed with 1N HCl (100 ml) and water (200 mL×2),dried over sodium sulfate, filtered, and concentrated. The product waspurified by silica gel chromatography with ethyl acetate:hexane (2:1) aseluent (R_(f)=0.2) to give the title compound(20.63 g, 75% yield). ¹HNMR (300 MHz, CD C₃) δ 7.65–7.7(m, 3H), 7.35–7.45 (m, 1H), 7.1–7.15 (m,2H), 4.39 (d, J=8.6:Hz, 2H), 4.05–3.85 (m, 5H), 3.86 (s, 3H), 1.61 (d,J=7.2 Hz), 1.25–0.11 (m, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 173.5 (d,J_(CP)=7.9 Hz), 157.7, 134.9, 133.7, 129.1, 128.8, 127.1, 126.1, 119.0,105.5, 62.6, 57.1 (d, J_(CP)=167.3 Hz), 55.2, 45.1, 18.3, 16.2. Anal.calcd. for C19H₁₇O₆P: C, 60.0; H, 6.62. Found C, 59.83; H, 6.41.

7b. Phosphonomethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

Bromotrimethylsilane (14 mL, 106.1 mol) was added to an ice-cooledsolution of the product of Example 7a in dichloromethane (250 ml). Theresulted solution was stirred in an ice-bath for 15 minutes and then atroom temperature overnight. The reaction was quenched with 1N HCl (80ml) and methanol (20 ml), stirred for 2 hours and the solvent wasevaporated. The residue was dissolved in EtOAc (300 mL), washed withwater (150 mL×2), dried over sodium sulfate, filtered, and concentratedto give a white solid. The solid was suspended in a solution ofchloroform (50 mL) and hexane (200 mL), filter, and the solid was washedwith hexane (100 mL) and dried under vacuum to give the title compound(12.73 g, 82% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.7–8.0 (m, 3H),7.4–7.5 (m, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.1–7.2 (m, 1H), 4.07–4.3 (m,4H), 3.96 (q, J=7.2 Hz, 1H), 3.86 (s, 3H), 1.49 (d, J=7.2 Hz, 3H). ¹³CNMR (75 MHz, DMSO-d₆) δ 173.4 (d, J_(CP)=7.5 Hz), 157.2, 135.4, 133.3,129.2, 128.4, 127.0, 126.3, 125.7, 118.7, 105.7, 62.6 (d, J_(CP)=160.2Hz), 55.2, 44.3, 18.7. Mass spectrum m/z 323 (M−H)⁻. Anal. calcd. forC₁₅H₁₅O₆P: C, 55.56; H, 5.28. Found C, 55.44; H, 5.32.

7c. 3-(Nitrooxy)propylamine nitric acid salt

A solution of 3-amino-1-propanol (6.17 g, 82.2 mmol) was added,drop-wise, to an ice-cooled solution of fuming nitric acid (90%, 12 mL)in acetic anhydride (50 mL). The reaction was stirred in an ice-bath for10 minutes and then at room temperature for 10 minutes. The solvent wasevaporated under vacuum at 40° C. The residue was stirred indiethylether (200 mL) until the product precipitated. The mixture wasfiltered and the white crystalline solid was dried in vacuo to give thetitle compound (12.1 g, 80% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 4.57(br. t, 2H), 2.8–3.0 (m, 2H), 1.98–1.93 (m, 2H). ¹³C NMR (75 MHz,DMSO-d₆) δ 70.9, 36.1, 24.5. MS m/z 121 (M−NO₃)⁺.

7d. Phosphonomethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate3-(nitrooxy)propylamine nitric acid salt

The product of Example 7c (0.264 g, 2.2 mmol) in dichloromethane (5 ml)was added to the product of Example 7b in methanol (5 mL) and theresulting solution stirred for 5 minutes. The solution was evaporated todryness and the solid was washed with diethyl ether (50 mL), dried undervacuum (0.43 g 90% yield) to give the title compound. Mp 123–4° C. ¹HNMR (300 MHz, DMSO-d₆) δ 7.8–7.7 (m, 3H) 7.43–7.4 (m, 1H), 7.27 (d,J=2.4 Hz, 1H), 7.15–7.11 (m, 1H), 4.57 (t, J=6.3 Hz, 4H), 4.1–3.7 (m,3H), 3.86 (s, 3H), 2.70 (t, J=6.9 Hz, 4H), 1.9–1.8 (m, 4H), 1.46 (d,J=7.1 Hz, 3H). ¹³C NMR (75 MHz, DMSO-d₆) δ 174.0 (d, J_(CP)=7.5 Hz),157.1, 135.9, 133.2, 129.1, 128.3, 126.8, 126.3, 125.5, 118.6, 105.6,71.4, 61.6 (d, J_(CP)=153.8 Hz), 55.1, 44.4, 36.1, 26.6, 18.8.

Example 8 Phosphonomethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate4-nitro-1-(nitrooxy)-2-((nitrooxy)methyl)but-2-ylamine salt

4-Nitro-1-(nitrooxy)-2-((nitrooxy)methyl)but-2-ylamine (0.734 g, 2.86mmol, the hydrochloride salt was prepared according to the procedure inU.S. Pat. No. 2,975,208 and then converted to the free acid in CH₂Cl₂ (5ml) was added to the product of Example 7b (0.39 g, 1.2 mmol) inmethanol (5 mL) and stirred for 5 minutes. The solution was evaporatedto dryness. The residue was dissolved in EtOAc (4 mL) and treated withhexane (40 mL). The solvent was removed and the resulting oil was driedunder vacuum to gave the title compound as a foam (0.563 g, 81% yield).Mp 39–41° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.8–7.7 (m, 3H), 7.43–7.4 (m,1H), 7.29 (d, J=2.4 Hz, 1H), 7.17–7.13 (m, 1H), 4.57 (s, 6H), 4.3–3.9(m, 2H), 3.96 (q, J=7.1 Hz, 1H), 3.86 (s, 3H), 1.46.(d, J=7.1 Hz, 3H).¹³C NMR (75 MHz, DMSO-d₆) δ 173.5 (d, J_(CP)=8.2 Hz), 157.2, 135.4,133.3, 129.1, 128.4, 126.9, 126.3, 125.6, 118.6, 105.7, 72.4, 61.6 (d,J_(CP)=153.8 Hz), 55.1, 53.8, 44.3, 18.7.

Example 9 (5-((Nitrooxy)methyl-1,3-dioxan-5-yl)methyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate 9a.5-(Hydroxymethyl)-1,3-dioxan-5-yl)methyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate

To a stirred solution of 1,3-dioxane-5,5-dimethanol (7.41 g, 50 mmol),(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.76 g, 25 mmol)and 1,3-dicyclohexylcarbodiimide (5.16 g, 25 mmol) in CH₂Cl₂ (150 mL)was added a catalytic amount of N,N-dimethylaminopyridine.(DMAP, 10 mg).The reaction mixture was stirred at ambient temperature for 15 hours,filtered, and the filtrate was concentrated. The crude product waspurified by chromatography (silica gel, 1:1 EtOAc:Hex) to give the titlecompound (7.92 g, 88% yield) as white prisms. Mp 106° C. ¹H NMR (300MHz, CDCl₃) δ 7.67–7.60 (m, 3H), 7.35–7.31 (m, 1H), 7.12–7.05 (m, 2H),4.66 (d, J=6.1 Hz, 1H), 4.61 (d, J=6.1 Hz, 1H), 4.24 (d, J=11.5 Hz, 1H),4.12 (d, J=11.5 Hz, 1H), 3.85 (s, 3H), 3.88–3.80 (m, 1H), 3.6–3.4 (m,41), 3.3–3.1 (m, 2H), 2.33 (br, 1H), 1.54 (d, J=7.1 Hz, 3H). ¹³C NMR (75MHz, CDCl₃) δ 175.3, 157.7, 135.1, 133.7, 129.2, 128.8, 127.2, 125.9,119.1, 105.5, 94.1, 69.2, 68.8, 63.1, 61.4, 55.2, 45.4, 39.6, 17.9. Massspectrum (API-TIS) m/z 361.2 (MH⁺).

9b. (5-((Nitrooxy)methyl)-1,3-dioxan-5-yl)methyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate

Acetic anhydride (6 mL) was cooled to <10° C. (internal temperature) andfuming nitric acid (90%, 2 mL. 43 mmol) was added keeping the sametemperature. A solution of the product of Example 9a (5.40 g, 15 mml) inTHF (100 mL) was added rapidly. After the addition was complete, thereaction mixture was stirred in the ice bath for 1 hour. The mixture wastaken up with EtOAc, washed with ice plus saturated aqueous NaHCO₃ (2×),brine, dried over Na₂SO₄, filtered, and concentrated. The resultingsolid was purified by crystallization from 1:2 EtOAc:Hex to give thetitle compound (4.81 g, 79% yield) as white flakes. Mp 98° C. ¹H NMR(300 MHz, CDCl₃) δ 7.72 (d, J=2.5 Hz, 1H), 7.68 (d, J=2.8 Hz, 1H), 7.63(s, 1H), 7.34 (dd, J=8.5, 1.7 Hz, 1H), 7.18–7.10 (m, 2H), 4.80 (d, J=6.1Hz, 1H), 4.56 (d, J=6.1 Hz, 1H), 4.38 (d, J=6.9 Hz, 1H), 4.32 (d, J=6.9Hz, 1H), 4.11 (d, J=11.6 Hz, 1H), 3.96 (d, J=11.6 Hz, 1H), 3.91 (s, 3H),3.88 (q, J=7.2 Hz, 1H), 3.68 (t, J=12.2 Hz, 2H), 3.51 (td, J=8.1, 3.5Hz, 2H), 1.59 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) 1173.9, 157.7,135.0, 133.8, 129.1, 128.8, 127.3, 125.9, 125.8, 119.2, 105.6, 94.2,70.6, 68.61, 68.58, 62.6, 55.3, 45.3, 37.9, 17.9. Mass spectrum(API-TIS) m/z 423.2 (M+NH₄ ⁺). Anal. Calcd. for C₂₀H₂₃NO₈: C, 59.25; H,5.72; N, 3.46. Found: C, 59.37; H, 5.81; N, 3.19.

Example 102,2-Bis(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate 10a.3-Hydroxy-2-(hydroxymethyl)-2-methylpropyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate

To a stirred solution of 1,1,1-tris(hydroxymethyl)ethane (13.1 g, 109mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.00 g,21.7 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimidehydrochloride (4.80 g, 25 mmol), and N,N-dimethylaminopyridine (DMAP, 20mg, catalytic amount) in acetonitrile (200 mL) was added triethylamine(4.2 mL, 30 mmol). The reaction mixture was stirred at ambienttemperature for 25 hours, filtered, and the filtrate was concentrated todryness. The residue was diluted with EtOAc, washed with 1N HCl (2×),saturated NaHCO₃, and brine, dried over Na₂SO₄, filtered, andconcentrated The resulting material was purified by crystallization (2×)from EtOAc/Hexanes (13 v:v) to give the title compound (4.72 g, 66%yield) as white flakes. Mp 105° C. ¹H NMR (300 CDCl₃) δ 7.72 (d, J=2.0Hz, 1H), 769 (d J 25 Hz, 1H), 7.66 (s, 1H), 7.39 (dd, J=8.5, 1.7 Hz,1H), 7.17–7.10 (m, 2H), 4.25 (d, J=11.3 Hz, 1H), 4.09 (d, J=11.3 Hz,1H), 3.90 (s, 3H), 3.88 (q, J=7.1 Hz, 1H), 3.46–3.25 (m, 4H), 2.65–2.55(m, 2H), 1.60 (d, J=7.1 Hz, 3H), 0.67 (s, 3H). ¹³C NMR (75 MHz, CDCl₃)8175.8, 157.7, 135.3, 133.8, 129.2, 128.9, 127.3, 126.0, 119.2, 105.6,67.7. 67.5, 66.8, 55.3, 45.6, 40.9, 18.1, 16.7. LRMS (API-TIS) m/z 350.2((M+NH₄)⁺).

10b. 2,2-Bis(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

Acetic anhydride (12 mL) was cooled to <10° C. (internal temperature)and fuming nitric acid (90%, 4 mL. 86 mmol) was added keeping the sametemperature. After 30 minutes a pre-cooled solution (−10° C.) of theproduct of Example 10a (4.72 g, 14.2 mmol) in THF (30 mL) was addedrapidly. After the addition was complete, the reaction mixture wasstirred in the ice bath for 15 minutes. The mixture was poured into iceplus EtOAc, washed with saturated NaHCO₃ (3×), dried over Na₂SO₄,filtered, and concentrated. Chromatography of the residue gave the titlecompound (3.60 g, 60% yield) as a yellow solid. Mp 67–68° C. ¹H NMR (300MHz, CDCl₃) δ 7.70 (d, J=2.0 Hz, 1H), 7.67 (d, J=2.5 Hz, 1H), 7.63 (s,1H), 7.34 (dd, J=8.5, 1.7 Hz, 1H), 7.17–7.10 (m, 2H), 4.21–4.10 (m, 4H),4.08 (d, J=11.5 Hz, 1H), 3.94 (d, J=11.5 Hz, 1H), 3.90 (s, 3H), 3.89 (q,J=7.2 Hz, 1H), 1.58 (d, J=7.2 Hz, 3H), 0.94 (s, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 173.8, 157.7, 134.9, 133.7, 129.1, 128.8, 127.3, 125.9, 125.8,119.2, 105.5, 73.1, 72.9, 65.1, 55.2, 45.3, 38.5, 17.8, 16.9. LRMS(API-TIS) m/z 423.2 ((M+H)⁺), 440.2 ((M+NH₄)⁺)

Example 113-(4-((Nitrooxy)methyl)phenylcarbonyloxy)-2-oxopropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate11a. 4-((Nitrooxy)methyl)benzoic acid

A solution of silver nitrate (17.73 g, 104.4 mmol) and α-bromo-p-toluicacid (10.84 g, 50.4 mmol) in THF (150 mL) and acetonitrile (150 mL) wasstirred at room temperature overnight and then at 50° C. for 1 hour. Thereaction mixture was then cooled to ambient temperature and stirred withbrine (150 mL) for 1 hour. The resulting mixture was filtered throughCelite and washed with water. The filtrate was concentrated and thenextracted with ethyl acetate. The combined organic layers were washedwith water brine, dried over Na₂SO₄, filtered, concentrated and driedunder vacuum. The crude product was washed with CH₂Cl₂ (50 mL) on aBuchner funnel then dried under vacuum to give the title compound as awhite solid (7.27 g, 73% yield). Mp:159–161° C. ¹H NMR (300 MHz,DMSO-d₆) δ 8.02 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 5.67 (s, 2H).¹³C NMR (75 MHz, DMSO-d₆) 8166.9, 137.3, 131.4, 129.7, 129.0, 74.3. Massspectrum (API-TIS) m/z 196 (MH)⁺.

11b 3-Hydroxy-2-oxopropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of 1,3-dicyclohexylcarbodiimide (2.84 g, 13.8 mmol) inacetone (40 mL) was added, drop-wise, to a solution of(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.14 g, 13.6mmol), 1,3-dihydroxy-acetone (3.11 g, 34.5 mmol) andN,N-dimethylaminopyridine (DMAP, 1.4 g, 11.5 mmol) in acetone (100 mL)and stirred at ambient temperature overnight. The byproduct,dicyclohexyl urea was removed by filtration. The filtrate wasconcentrated and the residue was dissolved in CH₂Cl₂ (150 mL), washedwith 3N HCl (150 mL), water (150 mL×3), brine, and dried over Na₂SO₄,filtered and concentrated. The product was separated by silica gelcolumn chromatography eluting with ethyl acetate/hexane (1:2, Rf=0.13)to obtained a mixture of the title compound and its dimer. The reactionmixture was treated with ethyl ether and the dimer was removed byfiltration. The filtrate was concentrated and dried under vacuum to givethe title compound as a sticky oil (1.59 g). The resulted material wasuse in the next step without further purification. Mass spectrum(API-TIS) m/z 303 (MH)⁺.

11e. 3-(4-((Nitrooxy)methyl)phenylcarbonyloxy)-2-oxopropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

1,3-Dicyclohexylcarbodiimide (1.18 g, 5.7 mmol) was added to a solutionof Example 11b (1.59 g, 5.26 mmol), Example 11a (1.03 g, 5.2 mmol) andN,N-dimethylaminopyridine (DMAP, 0.66 g, 5.36 mmol) in CHCl₃ (100 mL)and stirred at ambient temperature overnight. The byproduct,dicyclohexyl urea was removed by filtration. The filtrate wasconcentrated and the residue was dissolved in ethyl acetate (150 mL),washed with 3N HCl (100 mL), water (100 mL), brine, and dried overNa₂SO₄, filtered and concentrated. The resulting residue was treatedwith ethyl acetate (50 mL) and cooled to −30° C. in a dry-ice bath andthen filtered. The filtrate was concentrated, dissolved in ethyl ether(100 mL) and stirred until the product precipitated. The solid was driedunder vacuum to give the title compound (1.11 g, 44% yield). Mp 105–107°C. ¹H NMR (300 MHz, CDCl₃) δ 8.01–8.04 (m, 2H), 7.67–7.72 (m, 3H),7.4–7.43 (m, 3H), 7.09–7.14 (m, 2H), 5.42 (s, 2H), 4.85 (d, J=3.9 Hz,2H), 4.78 (d, J=3.5 Hz, 2H), 3.98 (q, J=7.1 Hz, 1H), 3.87 (s, 3H), 1.62(d, J=7.1 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) 6197.6, 173.8, 164.9, 157.6,137.8 134.7, 133.7, 130.3, 129.6, 129.2, 128.8, 128.4, 127.2, 126.0,119.0, 105.5, 73.4, 66.6, 66.5, 55.2, 45.0, 18.3, 14.1. Mass spectrum(API-TIS) m/z 482 (MH)⁺.

Example 122-Methyl-2nitro-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate12a.3-Hydroxy-2-methyl-2-nitropropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of 1,3-dicyclohexylcarbodiimide (4.23 g, 20.5 mmol),(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.34 g, 18.9mmol), and 2-nitro-2-methyl-1,3-propanediol (2.56 g, 19.0 mmol) inCH₂Cl₂ (50 mL) and TEF (50 mL) was stirred at ambient temperatureovernight. The solvent was evaporated and EtOAc (100 mL) was added tothe resulting crude material, cooled in a dry-ice bath and thebyproduct, dicyclohexyl urea was removed by filtration. The product wasseparated by silica gel column chromatography eluting with ethylacetate/hexane (1:3, Rf=0.1) to give the title compound (a mixture ofdiasteromers) as an oil (2.77 g, 42% yield). ¹H NMR (300 MHz, CDCl₃) δ7.69–7.60 (m, 3H), 7.34–7.3 (m, 1H), 7.14–7.08 (m, 2H), 4.44 (d, J=4.2Hz, 2H), 3.86 (s, 3H), 3.85 (q, J=7.2 Hz, 1H), 3.7 (m, 1H), 1.55 (d,J=7.2 Hz, 3H), 1.36 & 1.40 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.14,174.02, 157.57, 134.53, 134.51, 133.64, 129.13, 128.7, 127.17, 125.87,125.84, 119.0, 105.47, 89.53, 89.42, 64.67, 64.52, 64.19, 55.12, 45.04,18.25, 18.03, 17.82, 17.79. Mass spectrum (API-TIS) m/z 348 (MH)⁺.

12b.2-Methyl-2-nitro-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

Fuming nitric acid (90%, 120 mL, 2.9 mmol) was added to an ice-coldacetic anhydride (10 mL) and the mixture was stirred in the ice-bath for5 minutes then for an additional 5 minutes at ambient temperature. Thesolution was then added to an ice-cold solution of Example 12a (0.92 g,2.7 mmol) in EtOAc (10 mL). The reaction mixture was stirred in theice-bath for 5 minutes and then at ambient temperature for 2 hours. Asecond and equal portion of acetyl nitrate was added to the reactionmixture and then stirred for an additional hour. The reaction mixturewas washed with saturated NaHCO₃, water and brine, and dried overNa₂SO₄, filtered and concentrated under reduced pressure. The productwas separated by silica gel column chromatography eluting with ethylacetate/hexane (1:3, Rf=0.4) to give the title compound (a mixture ofdiasteromers) as a sticky oil (0.70 g, 67% yield). The oil solidifiedafter standing overnight at ambient temperature. Mp 58–74° C. ¹H NMR(300 MHz, CDCl₃) δ 7.69–7.59 (m, 3H), 7.32–7.28 (m, 1H), 1.15–71.08 (m,2H), 4.7–4.3 (m, 4H), 3.85 (s, 3H), 3.83 (q, J=7.1 Hz, 1H), 1.54 (m,3H), 1.43 & 1.42 (s, 3H), ¹³C NMR (75 MHz, CDCl₃) δ 173.07, 174.03,157.64, 134.37, 134.32, 133.68, 129.05, 128.66, 127.21, 127.17, 125.80,125.67, 119.06, 119.04, 105.41, 86.04, 85.99, 70.95, 70.63, 64.35,64.31, 55.04, 44.89, 44.84, 18.68, 18.55, 17.60. Mass spectrum (API-TIS)m/z 393.

Example 132-Nitro-3-(nitrooxy)-2-((nitrooxy)methyl)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate13a.3-Hydroxy-2-(hydroxymethyl)-2-nitropropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,4.27 g, 18.5 mmol), 2-hydroxymethyl-2-nitro-1,3-propanediol (2.89 g,19.1 mmol), N,N-dimethylaminopyridine (DMAP, 0.88 g, 7.2 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.86 g,25.4 mmol) and NEt(i-Pr)₂ (11 mL, 63.2 mmol) in acetone (100 mL) wasstirred at ambient temperature overnight. The reaction mixture wasevaporated to dryness and the residue was partitioned between 3N HCl(100 mL) and CH₂Cl₂ (200 mL×2). The combined organic layer was backwashed with water and brine, dried over Na₂SO₄, filtered, concentratedand dried under vacuum. The product was separated by silica gel columnchromatography eluting with ethyl acetate/hexane (gradient from 1:2 to1:1, Rf=0.1 in 1:2) to give the title compound as a white solid (2.48 g,39% yield). Mp 124–126° C. ¹H NMR (300 MHz, 10% CD₃OD/CDCl₃) δ 7.73–7.64(m, 3H), 7.37–7.33 (m, 1H), 7.17–7.12 (m, 2H), 4.44 (d, J=2.6 Hz, 2H),3.92 (s, 3H), 3.9–3.7 (m, 5H), 3.4 (br, 2H), 1.58 (d, J=7.2 Hz, 3H). ¹³CNMR (75 MHz, 10% CD₃OD/CDCl₃) δ 174.1, 157.4, 134.5, 133.5, 129.0,128.6, 127.0, 125.7, 118.8, 105.4, 92.4, 61.2, 60.1, 55.0, 45.0, 17.7.

13b.2-Nitro-3-(nitrooxy)-2-((nitrooxy)methyl)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

Fuming nitric acid (90%, 430 μL, 4.2 mmol) was added to ice-cold aceticanhydride (5 mL) and the mixture was stirred in the ice-bath for 5minutes, then for an additional 5 minutes at ambient temperature. Thesolution was then added to an ice-cold solution of Example 13a (1.51 g,4.2 mmol) in EtOAc (20 mL). The reaction was stirred in the ice-bath for5 minutes then at ambient temperature for 2 hours. A second portion ofacetyl nitrate, prepared from fuming nitric acid (90%, 100 μL, 2.4 mmol)in Ac₂O (2 mL), was added to the reaction mixture and stirred for anadditional 2 hours. The reaction mixture was washed with saturatedNaHCO₃, water and brine, and dried over Na₂SO₄, filtered andconcentrated. The product was separated by silica gel columnchromatography eluting with ethyl acetate/hexane (gradient form 1:3 to2:3, Rf=0.4 in 1:3) to give the title compound as a white solid (0.79 g,42% yield). Mp 69–71° C. ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.60 (m, 3H),7.31–7.24 (m, 1H), 7.18–7.11 (m, 2H), 4.72–4.43 (m, 6H), 3.91 (s, 3H),3.86 (q, J=7.2 Hz, 1H), 1.58 (d, J=7.2 Hz, 3H). ¹³C NMR(75 MHz, CDCl₃) δ172.8, 157.9, 134.1, 133.9, 129.1, 128.8, 127.5, 125.9, 125.5, 119.4,105.5, 86.2, 67.2, 66.9, 60.9, 55.3, 45.0, 17.6. Mass spectrum (API-TIS)m/z 454.

Example 142-(N-(2-(Nitrooxy)ethyl)carbamoyloxy)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate14a.2-(N-(2-Bromoethyl)carbamoyloxy)ethyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,0.74 g, 2.2 mmol), p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol)and 2-bromoethyl isocyanate (1.18 g, 7.9 mmol) in CH₂Cl₂ (100 mL) wasstirred at room temperature for 4 hours. The reaction mixture was washedwith saturated NaHCO₃ and extracted with CH₂Cl₂ (100 mL). The combinedorganic layer was washed with water, brine, dried over Na₂SO₄, filteredand concentrated. The product was separated by silica gel columnchromatography eluting with ethyl acetate/hexane (gradient form 2:3 to1:1, Rf=0.3 in 2:3) to give the title compound as an oil (1.57 g, 54%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.71–7.66 (m, 3H), 7.42–7.38 (m, 1H),7.16–7.08 (m, 2H), 5.0 (br, 1H), 4.27–4.19 (m, 4H), 3.89 (s, 3H), 3.88(q, J=7.2 Hz, 1H), 3.45–3.33 (m, 4H), 1.58 (d, J=7.2 Hz, 3H). ¹³C NMR(75 M CDCl₃) δ 174.3, 157.5, 155.6, 135.4, 133.5, 129.1 128.7, 126.9,126.1, 125.9, 118.9, 105.4, 62.6, 62.5, 55.2, 45.2, 42.5, 32.0, 18.3.Mass spectrum (API-TIS) m/z 424 (MH)⁺.

14b.2-(N-(2-(Nitrooxy)ethyl)carbamoyloxy)ethyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate

A solution of the product of Example 14a (1.57 g, 3.7 mmol) and AgNO₃(7.7 mmol) in acetonitrile (40 mL) was heated to 60° C. for 3 hours.After cooling to ambient temperature, brine (50 mL) was added and themixture was stirred for 30 minutes. The resulted mixture was filteredthrough Celite and the filtrate was extracted with CH₂Cl₂ (100 mL). Theorganic layer was washed with brine, dried over Na₂SO₄, filtered,concentrated and dried under vacuum. The product was separated by silicagel column chromatography eluting with ethyl acetate/hexane (1:2,Rf=0.22) to give the title compound. The product was recrystalized fromethyl ether (0.63 g, 41% yield). Mp 56–57° C. ¹H NMR (300 MHz, CDCl₃) δ7.72–7.66 (m, 3H), 7.42–7.38 (m, 1H), 7.17–7.11 (m, 2H), 4.9 (br, 1H),4.43 (t, J=5.0 Hz, 2H), 4.27–4.19 (m, 4H), 3.91 (s, 3H), 3.88 (q, J=7.2Hz, 1H), 3.37 (br. q, 2H), 1.58 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 174.3, 157.5, 155.8, 135.3, 133.5, 129.0 128.6, 126.9, 126.0,125.8, 118.9, 105.4, 71.5, 62.7, 62.4, 55.1, 45.1, 38.0, 18.2. Massspectrum (API-TIS) m/z 424 (M+NH₄)⁺.

Example 153-(2-(Nitrooxy)ethoxy)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate 15a.(2-Bromoethyl)nitrooxy

Sulfuric acid (14.55 g, 148 mmol) was cooled to 5° C. in an ice-waterbath. Fuming nitric acid (90%, 6.2 mL, 9.2 g, 146 mmol) was slowly addedwhile the temperature was maintained at <10° C. The resulting solutionwas stirred in the ice-water bath for 40 minutes. 2-Bromoethanol (4.8mL, 8.5 g, 67.7 mmol) was slowly added while maintaining the temperatureat <10° C. The reaction mixture was stirred in the ice-water bath fortwo hours, poured onto ice and extracted with ethyl ether. The organicphase was washed with water (3×), sodium bicarbonate solution (2×) andbrine. The organic phase was dried with magnesium sulfate, filtered, andconcentrated to give the title compound(10.48 g, 91% yield). ¹H NMR (300MHz, CDCl₃) δ 4.75 (t, J=6.4 Hz, 2H), 3.55 (t, J=6.4 Hz, 2H). ¹³C NMR(75 MHz, CDCl₃) δ 71.4, 25.1.

15b. 3-Hydroxyphenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate

To a suspension of ground resorcinol (6.7073 g, 60.915 mmol) in CH₂Cl₂(900 mL) was added (2S)-2-(6-methoxy(2-naphthyl))propanoic acid(naproxen, 4.4467 g, 19.311 mmol) and then1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC,5.3733 g, 28.030 mmol). The reaction mixture was stirred at ambienttemperature for 1 hour to give an oil phase and a solution phase. Thesolution phase was washed with water, brine, dried with magnesiumsulfate, filtered and then concentrated. The crude product was purifiedby chromatography (100% methylene chloride, then 1% methanol/99%methylene chloride, and then 2% methanol/98% methylene chloride) to givea mixture of the desired product and naproxen. The crude product wasdissolved in methylene chloride, washed with sodium bicarbonate solution(3×) and brine. The organic phase was dried over magnesium sulfate,filtered and concentrated to give the title compound (804.8 mg, 2.497mmol, 13% yield). Mp 143–144° C. ¹H NMR (300 MHz, CDCl₃) δ 7.73–7.70 (m,3H), 7.47 (d, J=8.3 Hz, 1H), 7.16–7.08 (m, 3H), 6.58 (d, J=7.7 Hz, 1H),6.52 (d, J=7.9 Hz, 1H), 6.43 (s, 1H), 4.06 (q, J=7.0 Hz, 1H), 3.90 (s,3H), 1.66 (d, J=7.0 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 173.43, 157.8,156.5, 151.7, 135.0, 133.8, 129.9, 129.3, 129.0, 127.4, 126.1, 126.0,119.1, 113.5, 113.1, 109.0, 105.7, 55.3, 45.6, 18.4. Mass spectum APIMS(IS, NH₄OAc) m/z 323 (M⁺H⁺), 340 (M+NH₄ ⁺), 345 (M+Na⁺), 662 (2M+NH₄ ⁺),984 (3M+NH₄ ⁺).

15c. 3-(2-(Nitrooxy)ethoxy)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate

To a solid mixture of the product of Example 15b (757.4 mg, 2.3495 mmol)and potassium carbonate powder (1.02 g, 7.38 mmol) under argon was addeddry acetone (100 mL) and then the product of Example 15a (0.45 mL, 810mg, 4.76 mmol). The resulting mixture was refluxed for two days and moreproduct of Example 15a (0.45 mL, 810 mg, 4.76 mmol) was added. Thereaction mixture was refluxed for one week and filtered. The filtratewas concentrated to dryness. The crude product was treated withmethylene chloride and water. The organic phase was dried over magnesiumsulfate, concentrated and purified by chromatography twice (100%methylene chloride) and (10% ethyl acetate/90% hexane) to give the titlecompound (30 mg, 0.073 mmol, 3% yield). Mp 88–91° C. ¹H NMR (300 MHz,CDCl₃) δ 7.77–7.70 (m, 3H), 7.49 (dd, J=8.6 Hz & 1.6 Hz, 1H), 7.26–7.14(m, 3H), 6.73 (dd, J=8.3 Hz, 2.3 Hz, 1H), 6.63 (dd, J=8.1 Hz, 1.8 Hz,1H), 6.54–6.52 (m, 1H), 4.75 (t, J=4.5 Hz, 1H), 4.17 (t, J=4.5 Hz, 2H),4.08 (q, J=7.1 Hz, 2H), 3.92 (s, 3H), 1.69 (d, J=7.2 Hz, 3H). ¹³C NMR(75 MHz, CDCl₃) δ 173.0, 158.6, 157.7, 151.8, 135.0, 133.8, 129.9,129.3, 128.9, 127.4, 126.15, 126.06, 119.1, 114.6, 112.0, 108.2, 105.6,70.7, 64.1, 55.3, 45.5, 18.5. Mass spectrum APIMS (IS, NH₄OAc) m/z 412(M+H⁺), 429 (M+NH₄ ⁺), 434 (M+Na⁺), 840 (2M+NH₄ ⁺).

Example 164-(2-(Nitrooxy)ethoxy)phenyl(2S)-2-(6-methoxy(2-naphthyl))propanoate16a. 4-Hydroxyphenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate

To (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 6.14 g, 26.64mmol) in methylene chloride (300 mL) was added1,3-dicyclohexylcarbodiimide (2.86 g, 13.84 mmol) in methylene chloride(20 mL). The reaction mixture was stirred at room temperature for 40minutes and then filtered. The filtrate was added to a stirringsuspension of hydroquinone (8.13 g, 73.84 mmol) in methylene chloride(1.6 L). N,N-dimethylaminopyridine (DMAP, 3.071 g, 25.14 mmol) wasadded. The reaction mixture was stirred at room temperature for 3 daysand then filtered. The filtrate was washed with 10% citric acid, brine,sodium bicarbonate solution and brine. The organic phase was dried overmagnesium sulfate, filtered, and concentrated. The crude product waspurified by chromatography (100% methylene chloride, then graduallyincreasing the percentage of methanol in methylene chloride from 0.5%,0.75%, 1%, 2%, 3% to 4%) to give the title compound (1.76 g, 41% yield).Mp 141–142 C. ¹H NMR (300 MHz, CDCl₃) δ 7.75–7.71 (m 3H), 7.48 (dd,J=8.6 Hz, 1.71 Hz, 1H), 7.17–7.14 (m, 2H), 6.84–6.79 (m, 2H), 6.74–6.68(d, 2H) 4.07 (q J=7.1 Hz, 1H), 3.92 (s, 3H), 1.67 (d, J=7.1 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ 174.0, 157.7, 153.4, 144.2, 135.1, 133.8, 129.3,129.0, 127.4, 126.11, 126.09, 122.2, 119.1, 115.9, 105.7, 55.3, 45.5,18.4. Mass spectrum APIMS (IS, NH₄OAc) m/z 323 (M+H⁺), 340 (M+NH⁺), 345(M+Na⁺), 662 (2M+NH₄ ⁺), 984 (3M+NH₄ ⁺),

16b. 4-(2-(Nitrooxy)ethoxy)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate

To a solid mixture of the product of Example 16a (1.29 g, 3.99 mmol) andpotassium carbonate (1.54 g, 11.11 mmol) under argon was added dryacetone (150 mL) and then the product of Example 15a (0.75 mL, 1.35 g,7.95 mmol). The reaction was refluxed for two days. More product ofExample 15a (0.75 mL, 1.35 g, 7.95 mmol) was added. The reaction mixturewas refluxed for ten days and then filtered. The filtrate wasconcentrated to dryness and treated with methylene chloride and water.The organic layer was dried over magnesium sulfate, filtered,concentrated and purified by chromatography twice (100% methylenechloride) and (10% ethylacetate/90% hexane) to give the title compound(49.2 mg, 3% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.76–7.70 (m, 3H), 7.48(dd, J=8.6 Hz, 1.7 Hz, 1H), 7.18–7.13 (m, 2H), 6.93–6.88 (m, 2H),6.84–6.78 (d, 2H), 4.75 (t, J=4.6 Hz, 2H), 4.16 (t, J=4.6 Hz, 2H), 4.07(q, J=7.1 Hz, 1H), 3.91 (s, 3H), 1.67 (d, J=7.1 Hz, 3H). ¹³C NMR (75MHz, CDCl₃) δ 173.4, 157.7, 155.5, 145.0, 135.1, 133.8, 129.3, 128.9,127.3, 126.09, 126.07, 122.4, 119.9, 115.1, 105.6, 70.8, 64.4, 55.3,45.5, 18.5. Mass spectrum APIMS (IS, NH₄OAc) m/z 412 (M+H⁺), 429 (M+NH₄⁺), 434 (M+Na⁺), 840 (2M+NH₄ ⁺).

Example 17(N-Methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate17a.((tert-Butyl)oxycarbonyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3g, 13.0 mmol), NaHCO₃ (1.4 g, 16.7 mmol) and tert-butyl bromoacetate(5.08 g, 26.0 mmol) in DMF (30 mL) was stirred at room temperature for 2days and the solvent was evaporated under high vacuo. The residue wasthen diluted with CH₂Cl₂, the solvent removed by filtration and theresidue was recrystallized from a mixture of CH₂Cl₂/EtOAc/Hex to givethe title compound as a white solid in quantitative yield. Mp 85–86° C.¹H NMR (300 MHz, CDCl₃) δ 7.69–7.70 (m, 3H), 7.43 (dd, J=1.6 and 8.6 Hz,1H), 7.10–7.15 (m, 2H), 4.47 (ABq, J_(AB)=15.7 Hz, Δν_(AB)=40.7 Hz, 2H),3.97 (q, J=7.2 Hz, 1H), 3.90 (s, 3H), 1.63 (d, J=7.2 Hz, 3H), 1.42 (s,9Ht). ¹³C NMR (75 MHz, CDCl₃) δ 174.2, 166.9, 157.8, 135.4, 133.9,129.5, 129.1, 127.3, 126.5, 126.3, 119.1, 105.8, 82.5, 61.7, 55.5, 45.3,28.1, 18.8. Mass spectrum (API-TIS) m/z 345 (MH⁺), 362 (MNH⁺).

17b. 2-((2S)-2-(6-Methoxy(2-naphthyl))propanoyloxy)acetic acid

Trifluoroacetic acid (8.4 mL) was added drop-wise to a solution of theproduct of Example 17a (4.8 g, 14 mmol) in CH₂Cl₂ (20 mL). The reactionmixture was stirred at room temperature for 2 days and the volatilematerial removed in vacuo. The residue after evaporation wasrecrystallized from EtOAc/Hex to give the title compound (2.7 g, 66%yield) as a white solid. Mp 122–123° C. ¹H NMR (300 MHz, CDCl₃) δ7.67–7.73 (m, 3H), 7.42 (d, J=9.1 Hz, 1H), 7.12–7.17 (m, 2H), 4.65 (ABq,J_(AB)=16.4 Hz, Δν_(AB)=34.3 Hz, 2H), 3.98 (q, J=7.1 Hz, 1H), 3.92 (s,3H), 1.63 (d, J=7.1 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.2, 173.0,157.9, 135.1, 133.9, 129.5, 129.1, 127.4, 126.4, 126.3, 119.2, 105.8,60.5, 55.5, 45.2, 18.7. Mass spectrum (API-TIS) m/z 289 (MH⁺), 306 (MNH₄⁺).

17c. Methyl(2-(nitrooxy)ethyl)ammonium nitrate

Methyl(2-(hydroxy)ethyl)amine (1.5 g, 20 mmol) in EtOAc (65 mL) wasadded dropwise to a mixture of fuming HNO₃ (6.3 g, 4.2 mL, 100 mmol) andAc₂O (16.3 g, 15.1 mL, 160 mmol) at −10° C. The reaction mixture wasstirred at −10° C. for 30 minutes and diluted with EtOAc and hexane. Theprecipitate was collected by filtration and washed with hexane to givethe title compound (2.79 g, 82% yield) as an off-white solid. Mp 58–62°C. ¹H NMR (300 MHz, d₆-DMSO) δ 4.59–4.67 (m, 2H), 4.64–4.73 (m, 2H),2.61 (bs, 3H). ¹³C NMR (75 MHz, d₆-DMSO) δ 59.8, 38.7, 24.4. Massspectrum (API-TIS) m/z 121 (MH⁺).

17d.(N-Methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of the product of Example 17b (1.03 g, 3.57 mmol), the productof Example 17c (0.72 g, 3.93 mmol) and N,N-dimethylaminopyridine (DMAP,0.44 g, 3.57 mmol) in CH₂Cl₂ (20 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.75 g,3.93 mmol). The reaction mixture was stirred at 0° C. for 3 hours,diluted with more CH₂Cl₂, washed with water, brine and dried overNa₂SO₄. The residue after filtration and evaporation was chromatographedon silica gel eluting with 1:3 to 1:2 to 1:1 EtOAc:Hex to give the titlecompound (0.71 g, 51% yield). Mp 80–81° C. ¹H NMR (300 MHz, CDCl₃) δ7.67–7.74 (m, 3H), 7.45 (dd, J=1.5 and 8.5 Hz, 1H), 7.08–7.18 (m, 2H),4.70 (ABq, J_(AB)=14.5 Hz, Δν_(AB)=58.2 Hz, 2H), 4.53–4.67 (m, 2H), 4.02(q, J=7.1 Hz, 1H), 3.92 (s, 3H), 3.56–3.77 (m, 2H), 2.97 (s, 3H) 1.65(d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.4, 167.1, 157.8, 135.3,133.9, 129.4, 129.0, 127.3, 126.4, 126.3, 119.1, 105.7, 71.3, 61.7,55.4, 46.3, 45.3, 36.0, 18.7. Mass spectrum (API-TIS) m/z 391 (MH⁺), 408(MNH⁺). Anal. calcd. for C₁₉H₂₂N₂O₇: C, 58.46; H, 5.68; N, 7.18. Found:C, 58.32; H, 5.55; N, 6.94.

Example 18(N-Ethyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate18a. Ethyl(2-(nitrooxy)ethyl)ammonium nitrate

Ethyl(2-(hydroxy)ethyl)amine (5 g, 56 mmol) in EtOAc (60 mL) was addeddrop-wise to a mixture of fuming HNO₃ (17.7 g, 11.8 mL, 280 mmol) andAc₂O (45.8 g, 42.3 mL, 448 mmol) at −10° C. The reaction mixture wasstirred at −10° C. for 30 minutes and diluted with EtOAc and hexane. Theoil layer was separated and dried in high vacuo to give the titlecompound (8.4 g, 76% yield) as a pale green oil. ¹H NMR (300 MHz,d₆-DMSO) δ 8.60–8.95 (bs, 2H), 4.84 (m, 2H), 3.37–3.49 (m, 2H),3.02–3.16 (m, 2H), 1.24 (t, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, d₆-DMSO) δ69.1, 43.6, 42.6, 11.0. Mass spectrum (API-TIS) m/z 135 (MH⁺).

18b.(N-Ethyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of the product of Example 17b (1.0 g, 3.47 mmol), the productof Example 18a (0.75 g, 3.82 mmol) and N,N-dimethylaminopyridine DMAP,0.42 g, 3.47 mmol) in CH₂Cl₂ (20 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.73 g,3.82 mmol). The reaction mixture was stirred at 0° C. for 3 hours,diluted with more CH₂Cl₂, washed with water, brine and dried overNa₂SO₄. The residue after filtration and evaporation was chromatographedon silica gel eluting with 1:2 to 1:1 EtOAc:Hex to give the titlecompound (0.4 g, 29% yield). Mp 60–61° C. ¹H NMR (300 MHz, CDCl₃) δ7.65–7.74 (m, 3H), 7.44 (dd, J=1.5 and 8.5 Hz, 1H), 7.06–7.17 (m, 2H),4.70 (ABq, J_(AB)=14.4 Hz, Δν_(AB)=64.9 Hz, 2H), 4.54–4.65 (m, 2H), 4.01(q, J=7.1 Hz, 1H), 3.91 (s, 3H), 3.50–3.72 (m, 21H), 3.26 (q, J=7.2 Hz,2H), 1.64 (d, J=7.2 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 174.5, 166.9, 157.8, 135.3, 133.9, 129.4, 129.0, 127.3, 126.4,126.3, 119.1, 105.7, 71.0, 61.5, 55.4, 45.3, 43.9, 43.3, 18.7, 14.0.Mass spectrum (API-TIS) m/z 405 (MH⁺), 422 (MNH₄ ⁺). Anal. calcd. forC₂₀H₂₄N₂O₇: C, 59.40; H, 5.98; N, 6.93. Found: C, 59.28; H, 5.81; N,6.70.

Example 192-(4-((Nitrooxy)methyl)piperidyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate19a. Nitrooxy(4-piperidylmethyl)hydrogen nitrate

4-Piperidylmethan-1-ol (2.5 g, 21.7 mmol) in a mixture of EtOAc (25 mL)and CH₂Cl₂ (5 mL) was added drop-wise to a mixture of fuming HNO₃ (6.83g, 4.6 mL, 109 mmol) and Ac₂O (17.7 g, 16.3 mL, 174 mmol) at −10° C. Thereaction mixture was stirred at −10° C. for 30 minutes and diluted withEtOAc and hexane. The precipitate was collected by filtration and washedwith hexane to give the title compound (2.5 g, 52% yield) as a palegreen solid. Mp 51–53° C. ¹H NMR (300 MHz, d₆-DMSO) δ 8.45–8.75 (bs,1H), 8.10–8.40 (bs, 1H), 4.44 (d, J=6.4 Hz, 2H), 3.22–3.35 (m, 2H),2.80–2.98 (m, 2H), 1.96–2.15 (m, 1H), 1.75–1.89 (m, 2H), 1.40–1.52 (m,2H). ¹³C NMR (75 MHz, d₆-DMSO) δ 76.4, 42.7, 31.2, 24.9. Mass spectrum(API-TIS) m/z 161 (MH⁺). Anal. calcd. for C₆H₁₃N₃O₆: C, 32.29; H, 5.87;N, 18.83. Found: C, 32.03; H, 5.78; N, 18.73.

19b. 2-(4-((Nitrooxy)methyl)piperidyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of the product of Example 17b (1.5 g, 5.21 mmol), the productof Example 19a (1.16 g, 5.21 mmol) and N,N-dimethylaminopyridine (DMAP,0.63 g, 5.21 mmol) in CH₂Cl₂ (30 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (1.0 g,5.21 mmol). The reaction mixture was stirred at 0° C. for 3 hours,diluted with CH₂Cl₂, washed with water, brine and dried over Na₂SO₄. Theresidue after filtration and evaporation was chromatographed on silicagel eluting with 1:2 to 1:1 EtOAc:Hex to give the title compound (1.74g, 78% yield) as a white solid. Mp 94–95° C. ¹H NMR (300 MHz, d₆-DMSO) δ7.75–7.82 (m, 3H), 7.44 (dd, J=1.3 and 8.5 Hz, 1H), 7.30 (d, J=2.5 Hz,1H), 7.16 (dd, J=2.5 and 8.9 Hz, 1H), 4.65–4.89 (m, 2H), 4.35 (bd, J=6.4Hz, 2H), 4.21–4.32 (m, 1H), 4.01 (q, J=7.1 Hz, 1H), 3.86 (s, 3H),3.55–3.73 (m, 1H), 2.81–3.02 (m, 1H), 2.45–2.63 (m, 1H), 1.87–2.03 (m,1H), 1.55–1.72 (m, 2H), 1.51 (d, J=7.1 Hz, 3H), 0.90–1.22 (m, 2H). ¹³CNMR (75 MHz, d₆-DMSO) δ 173.5, 164.3, 157.2, 135.5, 133.3, 129.1, 128.4,126.9, 126.5, 125.8, 118.7, 105.6, 76.9, 61.8, 55.1, 44.3, 43.2, 33.2,28.2, 27.5, 18.6. Mass spectrum (API-TIS) m/z 431 (MH⁺), 448 (MNH₄ ⁺)Anal. calcd. for C₂₂H₂₆N₂O₇: C, 61.39; H, 6.09; N, 6.51. Found: C,61.24; H, 5.98; N, 6.40.

Example 20(N-Methyl-N-(((2-(nitrooxy)ethyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate 20a.(N-(((tert-Butyl)oxycarbonyl)methyl)-N-methylcarbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of the product of Example 17b (10 g, 34.7 mmol), sarcosinetert-butyl ester hydrochloride (6.3 g, 34.7 mmol) andN,N-dimethylaminopyridine (DMAP, 4.24 g, 34.7 mmol) in CH₂Cl₂ (125 mL)at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (6.7 g,34.7 mmol). The reaction mixture was stirred at room temperature for 16hours, diluted with CH₂Cl₂, washed with water, brine and dried overNa₂SO₄. The residue after filtration and evaporation was chromatographedon silica gel eluting with 1:9 to 1:1 EtOAc:hexane to give the titlecompound (11.8 g, 82% yield) as a white solid. Mp 103–104° C. ¹H NMR(300 MHz, CDCl₃) δ 7.65–7.77 (m, 3H), 7.44 (dd, J=1.3 and 8.9 Hz, 1H),7.03–7.18 (m, 2H), 4.74 (ABq, J_(AB)=14.5 Hz, Δν_(AB)=64.7 Hz, 2H),3.72–4.19 (m, 3H), 3.90 (s, 3H), 2.93 (s, 3H), 1.63 (d, J=7.1 Hz, 3H),1.45 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 174.3, 168.0, 167.1, 157.8,135.5, 133.9, 129.5, 129.1, 127.3, 126.5, 126.3, 119.0, 105.8, 82.2,61.5, 55.4, 51.6, 45.3, 35.3, 28.2, 18.8. Mass spectrum (API-TIS) m/z416 (MH⁺), 433 (MNH₄ ⁺), 438 (MNa⁺).

20b.2-(2-((2S)-2-(6-Methoxy(2-naphthyl))propanoyloxy)-N-methylacetylamino)aceticacid

Trifluoroacetic acid (5 mL) was added drop-wise to a solution of theproduct of Example 20a (3.54 g, 8.5 mmol) in CH₂Cl₂ (15 mL). Thereaction mixture was stirred at room temperature for 24 hours and thevolatile material removed in vacuo. The residue, after evaporation, wasrecrystallized from CH₂Cl₂/EtOAc/hexane to give the title compound (2.55g, 83% yield) as a white solid. Mp 174–175 C. ¹H NMR (300 MHz, d₆-DMSO)δ 7.76–7.80 (m, 3H), 7.42–7.45 (m, 1H), 7.27–7.29 (m, 1H), 7.15 (dd,J=2.5 and 8.5 Hz, 1H), 4.84 (ABq, J_(AB)=15.1 MHz, Δν_(AB)=26.9 Hz, 2H),3.93–4.12 (m, 3H), 3.87 (s, 3H), 2.94 (s, 3H), 1.51 (d, J=7.1 Hz, 3H).¹³C NMR (75 MHz, d₆-DMSO) δ 173.4, 170.5, 166.6, 157.2, 135.5, 133.3,129.2, 128.4, 126.9, 126.5, 125.8, 118.7, 105.8, 61.4, 55.2, 48.9, 44.3,34.5, 18.7. Mass spectrum (API-TIS) m/z 360 (MH⁺), 377 (MNH₄ ⁺), 382(MNa⁺). Anal. calcd. for C₁₉H₂₁NO₆: C, 63.50; H, 5.89; N, 3.90. Found:C, 63.33; H, 5.90; N, 3.89.

20c.(N-(((2-Hydroxyethyl)oxycarbonyl)methyl)-N-methylcarbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of the product of Example 20b (0.5 g, 1.4 mmol),N,N-dimethyl aminopyridine (DMAP, 84.9 mg, 0.69 mmol) and ethyleneglycol (1.6 g, 27.8 mmol) in CH₂Cl₂ (4 mL) was added drop-wise asolution of DCC (0.36 g, 1.7 mmol) in CH₂Cl₂ (2 mL). The reactionmixture was stirred at room temperature for 16 hours. The precipitatewas filtered. The residue after evaporation of the solvent wasredissolved in EtOAc, washed with water, brine and dried over Na₂SO₄.The residue after filtration and evaporation was chromatographed onsilica gel eluting with 1:1:0.1 EtOAc:hexane:MeOH to-give the titleproduct (0.4 g, 71% yield) as a white solid. Mp 113–114° C. ¹H NMR (300MHz, CDCl₃) δ 7.67–7.73 (m, 3H), 7.44 (dd, J=1.6 and 8.6 Hz, 1H),7.11–7.15 (m, 2H), 4.74 (ABq, J_(AB)=14.6 Hz, Δν_(AB)=55.9 Hz, 2H),4.22–4.31 (m, 2H), 4.09–4.12 (bs, 2H), 4.01 (q, J=7.2 Hz, 1H), 3.90 (s,3H), 3.74–3.83 (m, 2H), 2.99 (s, 3H), 2.40 (bs, 1H), 1.64 (d, J=7.2 Hz,3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.6, 168.9, 167.6, 157.8, 135.3, 133.9,129.4, 129.0, 127.3, 126.5, 126.3, 119.1, 105.8, 67.1, 61.6, 60.9, 55.4,50.2, 45.3, 35.5, 18.6. Mass spectrum (API-TIS) m/z 404 (MH⁺), 421 (MNH₄⁺). Anal. calcd. for C₂₁H₂₅NO₇. 1 mol H₂O: C, 59.85; H, 6.46; N, 3.32.Found: C, 59.94; H, 6.15; N, 3.39.

20d.(N-Methyl-N-(((2-(nitrooxy)ethyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A suspension of the product of Example 20c (0.26 g, 0.64 mmol) in EtOAc(0.28 mL) was added drop-wise to a mixture of fuming HNO₃ (61.3 mg, 41mL, 0.97 mmol) and Ac₂O (148 μg, 137 μL, 1.45 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 3 hours. Then an additionalice cold mixture of fuming HNO₃ (61.3 mg, 41 μL, 0.97 mmol) and Ac₂O(148 mg, 137 μL, 1.45 mmol) was added drop-wise to the reaction mixtureat 0° C. The stirring was continued for another 2 hours. The reactionmixture was diluted with EtOAc and washed with ice cold saturatedNaHCO₃, water and dried over Na₂SO₄. The residue after filtration andevaporation was chromatographed on silica gel eluting with 1:1:0.1EtOAc:hexane:MeOH to give the title compound (0.2 g, 69% yield) as awhite solid. Mp 71–73 C. ¹H NMR (300 MHz, CDCl₃) δ 7.66–7.75 (m, 3H),7.44 (dd, J=1.6 and 8.5 Hz, 1H), 7.08–7.17 (m, 2H), 4.76 (ABq,J_(AB)=14.6 Hz, Δν_(AB)=59.7 Hz, 2H), 4.64–4.69 (m, 2H), 4.39–4.42 (m,2H), 4.14 (ABq, JAB=17.4 Hz, Δν_(AB)=32.0 Hz, 2H), 3.93–4.07 (m, 1H),3.91 (s, 3H), 2.98 (s, 3H), 1.64 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 174.3, 168.6, 167.4, 157.8, 135.4, 133.9, 129.5, 129.0, 127.3,126.5, 126.3, 119.1, 105.7, 70.2, 61.5, 61.1, 55.4, 49.5, 45.3, 35.3,18.7. Mass spectrum (API-TIS) m/z 449 (MH⁺), 466 (MNH₄ ⁺). Anal. calcd.for C₂₁H₂₄N₂O₉: C, 56.25; H, 5.39; N, 6.25. Found: C, 56.00; H, 5.17; N,6.09.

Example 21(N-Methyl-N-(((3-(nitrooxy)propyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate21a.(N-(((3-Hydroxypropyl)oxycarbonyl)methyl)-N-methylcarbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of the product of Example 20b (0.5 g, 1.4 mmol),N,N-dimethylaminopyridine (DMAP, 84.9 mg, 0.69 mmol) and 1,3-propanediol(2.1 g, 27.8-mmol) in CH₂Cl₂ (4 mL) was added drop-wise a solution ofDCC (0.36 g, 1.7 mmol) in CH₂Cl₂ (2 mL). The reaction mixture wasstirred at room temperature for 16 hours. The precipitate was filtered.The residue after evaporation of the solvent was redissolved in EtOAc,washed with water, brine and dried over Na₂SO₄, filtered and evaporated.The residue was chromatographed on silica gel eluting with 1:1:0.1EtOAc:hexane:MeOH to give the product (0.35 g, 60% yield) as a whitesolid. Mp 80–82° C. ¹H NMR (300 MHz, CDCl₃) δ 7.40–7.73 (m, 3H), 7.43(dd, J=1.5 and 8.6 Hz, 1H), 7.07–7.15 (m, 2H), 4.75 (ABq, J_(AB)=14.6Hz, Δν_(AB)=57.7 Hz, 2H), 4.28 (t, J=5.9 Hz, 2H), 3.95–4.20 (m, 3H),3.90 (s, 3H), 3.61–3.72 (m, 2H), 2.97 (s, 3H), 1.78–2.00 (m, 3H), 1.63(d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.4, 169.1, 167.3, 157.8,135.3, 133.8, 129.4, 129.0, 127.2, 126.4, 126.2, 119.0, 105.7, 62.4,61.5, 59.0, 55.4, 49.8, 45.2, 35.3, 31.6, 18.7. Mass spectrum (API-TIS)m/z 418 (M<), 435 (MNH₄ ⁺), 440 (MNa⁺). Anal. calcd. for C₂₂H₂₇NO₇¼molH₂O: C, 62.62; H. 6.58; N, 3.32. Found: C, 62.35; H, 6.47; N, 3.44.

21 b.(N-Methyl-N-(((3-(nitrooxy)propyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A suspension of the product of Example 21a (355 mg, 0.85 mmol) in EtOAc(7.6 mL) was added drop-wise to a mixture of fuming HNO₃ (80.9 mg, 54μL, 1.28 mmol) and Ac₂O (196 mg, 181 μL, 1.92 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 1.5 hours. Then an additionalice cold mixture of fuming HNO₃ (80.9 mg, 54 μL, 1.28 mmol) and Ac₂O(196 mg, 181 μL, 1.92 mmol) was added drop-wise to the reaction mixtureat 0° C. The stirring was continued for an additional hour. The reactionmixture was diluted with EtOAc and washed with ice cold saturatedNaHCO₃, water and dried over Na₂SO₄. The residue after filtration andevaporation was chromatographed on silica gel eluting with 1:1:0.1EtOAc:hexane:MeOH to give the title compound (0.34 g, 86% yield) as awhite solid. Mp 41–43° C. ¹H NMR (300 MHz, CDCl₃) δ 7.60–7.73 (m, 3H),7.45 (dd, J=1.7 and 8.6 Hz, 1H), 7.09–7.17 (m, 2H), 4.76 (ABq,J_(AB)=14.6 Hz, Δν_(AB)=59.0 Hz, 2H), 4.52 (t, J=6.2 Hz, 2H), 4.24 (t,J=6.0 Hz, 2H), 4.10 (ABq, J_(AB)=17.4 Hz, Δν_(AB)=30.4 Hz, 2H),3.93–4.04 (m, 1H), 3.91 (s, 3H), 2.98 (s, 3H), 2.02–2.11 (m, 2H), 1.64(d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.3, 168.8, 167.4, 157.7,135.4, 133.8, 129.4, 129.0, 127.3, 126.5, 126.3, 119.1, 105.7, 69.9,61.5, 61.3, 55.4, 49.7, 45.3, 35.3, 26.4, 18.7. Mass spectrum (API-TIS)m/z 463 (MH⁺), 480 (MNH₄ ⁺). Anal. calcd. for C₂₂H₂₆N₂O₉: C, 57.14; H,5.67; N, 6.06. Found: C, 56.91; H, 5.86; N, 6.02.

Example 22(N-Methyl-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methyl)carbamoyl)methyl(2S)-2-(6methoxy(2-naphthyl))propanoate22a. 2-(Nitrooxy)ethylammonium nitrate

2-Hydroxyethylamine (5 g, 81.9 mmol) in EtOAc (40 mL) was addeddrop-wise to a mixture of fuming HNO₃ (18 g, 12 mL, 0.29 mol) and Ac₂O(54 g, 50 mL, 0.53 mol) at −10° C. The reaction mixture was stirred at0° C. for 10 minutes and at room temperature for 10 minutes. The solventwas evaporated in high vacuo at 40° C. The residue was sonicated withether. The solid was filtered and washed with hexane to give the titlecompound as a white solid. Mp 92–94° C. ¹H NMR (300 MHz, d₆-DMSO)67.71–8.25 (bs, 3H), 4.72 (t, J=5.0 Hz, 2H), 3.23 (d, J=5.0 Hz, 2H). ¹³CNMR (75 MHz, d₆-DMSO) δ 70.9, 37.4.

22b.(N-Methyl-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of the product of Example 20b (0.5 g, 1.39 mmol), the productof Example 22a (0.26 g, 1.53 mmol) and N,N-dimethylaminopyridine (DMAP,0.17 g, 1.39 mmol) in CH₂Cl₂ (8 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.29 g,1.53 mmol). The reaction mixture was stirred at 0° C. for 3 hours,diluted with CH₂Cl₂, washed with water, brine and dried over Na₂SO₄. Theresidue after filtration and evaporation was chromatographed on silicagel eluting with 1:2 EtOAc:hexane to 1:1:0.1 EtOAc: hexane:MeOH to givethe title compound (0.61 g, 89% yield) as a white solid. Mp 79–81° C. ¹HNMR (300 MHz, CDCl₃) δ 7.67–7.75 (m, 3H), 7.35–7.45 (m, 1H), 7.07–7.17(m, 2H), 6.53–6.60 (bs, 1H), 4.68 (ABq, J_(AB)=14.3 MHz, Δν_(AB)=39.6Hz, 2H), 4.47 (t, J=5.3 HZ, 2H), 3.93–4.07 (m, 3H), 3.91 (s, 3H),3.46–3.58 (m, 2H), 3.01 (bs, 3H), 1.63 (d, J=7.1 Hz, 3H). ¹³C NMR (75MHz, CDCl₃) δ 175.0, 168.9, 167.9, 157.9, 135.2, 133.9, 129.4, 129.0,127.3, 126.4, 126.3, 119.2, 105.8, 71.3, 61.6, 55.4, 52.3, 45.2, 37.0,35.8, 18.6. Mass spectrum (API-TIS) m/z 448 (MH⁺), 465 (MNH₄).

Example 23((2-(Nitrooxy)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate23a.((2-Hydroxyethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate

The product of Example 17b (1.48 g, 5.1 mmol), ethylene glycol (1.52 mL,25.7 mmol), and N,N-dimethylaminopyridine (DMAP, 124.1 mg, 1.0 mmol)were dissolved in 20 mL of CH₂Cl₂ and a solution of1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC,1.17 g, 6.2 mmol) in 10 mL of CH₂Cl₂ was added. The mixture was stirredat room temperature for 4.5 hours. Aqueous work-up followed by dryingover MgSO₄ and removal of the solvent under reduced pressure gave awhite solid (1.7 g) which was purified via column chromatography onsilica gel eluting with 2:1 hexanes/EtOAc. Recrystalization fromCH₂Cl₂/hexanes gave the title compound (1.2 g, 68% yield) as a whitesolid. Mp 87–90 C. ¹H NMR (300 MHz, CDCl₃); 87.73–7.70 (m, 3H), 7.43(dd, J=1.8 Hz, 8.5), 1H), 7.41–7.16 (m, 2H), 4.63 (d, J=2.3 Hz, 2H),4.24–4.21 (m, 2H), 3.98 (q, J=7.2 Hz, 1H), 3.91 (s, 3H), 3.71–3.69 (m,2H), 1.63 (d, J=7.2 Hz, 3H); Mass spectrum (API-TIS) m/z 350 (M+18)

23b.((2-(Nitrooxy)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate

Acetic anhydride (742.2 μl, 8.0 mmol) was cooled to 0° C. and fumingnitric acid (90%, 244.2 μL, 5.2 mmol) was added. The mixture was stirredfor 20 minutes at 0° C. The fuming nitric acid/acetic anhydride mixturewas rapidly added drop-wise to a solution of the product of Example 23a(1.2 g, 3.5 mmol) dissolved in EtOAc (15 mL) at 0° C. and the resultingmixture was stirred at 0° C. for 3 hours. The mixture was allowed towarm to room temperature and saturated NaHCO₃ was added. The organicswere separated and the aqueous portion extracted with EtOAc. Thecombined organic extracts were washed with brine, and dried over MgSO₄.The sample was filtered through a silica gel plug eluting with 2:1hexanes/EtOAc to give the title compound (882.6 mg, 74% yield) as ayellow oil which solidified on standing. Mp 44–45° C. ¹HNMR (300 MHz,CDCl₃); δ 7.72–7.69 (m, 3H), 7.42 (dd, J=1.8, 8.5 Hz, 1H), 7.16–7.10 (m,2H), 4.62 (d, J=5.8 Hz, 2H), 4.57–4.53 (m, 2H), 4.38–4.43 (m, 2H), 3.98(q, J=7.2 Hz, 1H), 3.91 (s, 3H), 1.63 (d, J=7.2 Hz, 3H). Mass spectrum(API-TIS) m/z 378 (MH⁺)

Example 24(N-(3-(Nitrooxy)propyl)carbamoyl)methyl2-(6-methoxy-2-naphthyl)propanoate

The product of Example 17b (1.7 g, 5.9 mmol), the product of Example 7c(1.3 g, 7.1 mmol), Et₃N (2.6 mL, 18.9 mmol) andN,N-dimethylaminopyridine (DMAP, 142.7 mg, 1.2 mmol) were dissolved inCH₂Cl₂ (30 mL) and a solution of 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 1.4 g, 7.1 mmol) in 5mL CH₂Cl₂ was added drop-wise. The mixture was stirred at roomtemperature overnight. The sample was washed with H₂O (35 mL), 1N HCl (3mL), and brine, and dried over MgSO₄. The solvent was removed underreduced pressure to give a yellow oil (2.1 g). The oil was purified viacolumn chromatography on silica gel eluting with 1:1 hexanes/EtOAc togive a beige solid. Trituration in Et₂O gave the title compound as abeige solid (861.3 mg, 37% yield). Mp 51–53° C. ¹H NMR (300 MH, CDCl₃);δ 7.77–7.71 (m, 3H), 7.41(dd, J=1.8, 8.5 Hz, 1H), 7.19 (dd, J=2.5, 8.9,1H), 7.14 (d, J=2.5 Hz, 2H), 5.29–5.24 (m; 1H), 4.80 (dJ=15.6 Hz, 1H),4.33 (d, J=15.6 Hz, 1H), 4.36–4.05 (m, 2H), 3.96 (q, J=7.1 Hz, 1H), 3.93(s, 3H), 2.95–2.78 (m, 2H), 1.64 (d, J=7.1 Hz, 3H), 1.39–1.31 (m, 2H).Mass spectrum (API-TIS) m/z 391 (MH⁺)

Example 25((2-((2-(nitrooxy)ethyl)sulfonyl)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate25a.((2-(2-Hydroxyethylthio)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate.

The product of Example 17b (1.02 g, 66.4 mmol), 2,2′-thiodiethanol (1.76mL, 17.7 mmol) and N,N-dimethylaminopyridine (DMAP, 85.5 mg, 0.71 mmol)were dissolved in 10 mL CH₂Cl₂ and a solution of1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC,810.4 mg, 4.24 mmol) in 5 mL of CH₂Cl₂ was added. The mixture wasallowed to stir overnight. Aqueous work-up followed by drying over MgSO₄and removal of the solvent under reduced pressure gave a yellow oil(1.65 g) which was purified via column chromatography on silica geleluting with 2:1 hexanes/EtOAc to give the product as a white solid (1.0g, 75% yield). ¹H NMR (300 MHz, CDCl₃); δ 7.72–7.69 (m, 3H), 7.43 (dd,J=1.6, 8.4 Hz, 1H), 7.16–7.11 (m, 2H), 4.61 (d, J=6.0 Hz, 2H), 4.24 (t,J=6.9 Hz, 2H), 3.98 (q, J=7.1 Hz, 1H), 3.90 (s, 3H), 3.69 (t, J=6.0 Hz,2H), 2.69–2.09 (m, 2H), 1.62 (d, J=7.1 Hz, 3H). Mass spectrum (API-TIS)m/z 391 (MH⁺).

25b.((2-((2-Hydroxyethyl)sulfonyl)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate

The product of Example 25a (1.03 g, 2.62 mmol) was dissolved in CH₂Cl₂(25 mL) and cooled to 0° C. OXONE® (3.23 g, 5.25 mmol) was added and themixture was stirred at 0° C. for 3 hours and warmed to room temperature.Additional OXONE® was added (6.05 g, 2.31 mmol) and the mixture stirredat room temperature for 6 hours. Aqueous work-up followed by removal ofthe solvent under reduced pressure and recrystallization of the residuefrom CH₂Cl₂/hexanes gave the title compound as off-white crystals (43.9mg, 40% yield). ¹H NMR (300 MHz, CDCl₃); δ 7.74–7.68 (m, 3H), 7.41 (dd,J=1.8, 8.5 Hz, 1H), 7.17–7.12 (m, 2H), 4.62 (br s, 2H), 4.57, (t, J=5.7Hz, 2H), 4.03 (t, J=5.1 Hz, 2H), 3.96 (q, J=7.1 Hz, 1H), 3.91 (s, 3H),3.37–3.33 (br t, 2H), 2.11 (t, J=5.1 Hz, 2H), 1.62 (d, J=7.1 Hz, 3H);Mass spectrum (API-TIS) m/z 442 (M+18)

25c.((2-((2-(nitrooxy)ethyl)sulfonyl)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate

Acetic anhydride (1.00 g, 11.5 mmol) was cooled to 0° C. and fumingnitric acid (90%, 351.2 μL, 7.52 mmol) was added. The fuming nitricacid/acetic anhydride mixture was added drop-wise rapidly to a solutionof the product of Example 25b (2.13 g, 5.02 mmol) in EtOAc (10 mL) at 0°C. and the resulting mixture stirred for 3 hours at 0° C. CH₂Cl₂ (7 mL)and NaHCO₃ (3 mL) were cooled to 0° C. and the reaction mixture wasadded to it. The aqueous portion was separated and extracted withadditional CH₂Cl₂ (10 mL) and the combined organic extracts were washedwith brine, and dried over MgSO₄. The solvent was removed under reducedpressure and the resulting residue purified via column chromatography onsilica gel eluting with 2:1 hexanes/EtOAc followed by 1:1 hexanes/EtOActo give the title compound (29.7 mg, 1.3% yield) as a white solid. ¹HNMR (300 MHz, CDCl₃); δ 7.74–7.68 (m, 3H), 7.41 (dd, J=1.7, 8.5 Hz, 1H),7.17–7.12 (m, 2H), 4.74 (t, J=5.9 Hz, 2H), 4.61 (s, 3H), 4.53 (t, J=5.5Hz 2H), 3.97 (q, J=7.2 Hz, 1H), 3.91 (s, 3H), 3.25–3.17 (m, 4H), 1.61(d, J=7.2 Hz, 3H); Mass spectrum (API-TIS) m/z 488 (M+18)

Example 26 (1S, 5S, 2R,6R)-6-(Nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl)oxycarbonyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of the product of Example 17b (1.11 g, 3.85 mmol) and(2S)-7-(nitrooxy)-4,8-dioxabicyclo(3.3.0) octan-2-ol (773 mg (4.04 mmol)in anhydrous dichloromethane (25 mL) were added1-ethyl-3-(3-dimethylaminopropyl) carbamide hydrochloride (EDAC) (812 mg(4.24 mmol) and a catalytic amount of N,N-dimethylaminopyridine (DMAP)at room temperature under nitrogen atmosphere. The reaction mixture wasstirred at room temperature overnight, then diluted with CH₂Cl₂, washedwith H₂O, brine, dried over sodium sulfate, filtered, and the organicextracts were evaporated in vacuo to give a white foam. The solid wasrecrystallized from boiling EtOAc/hexanes to give the title compound(1.26 g, 71% yield) as a white crystalline solid: Mp 104–106° C. ¹H NMR(CDCl₃) δ 7.73 (m, 3H), 7.45 (m, 1H), 7.15 (m, 2H), 5.15 (m, 1H), 5.02(m, 1H), 4.60 (ABq, 2H, J_(AB)=16.0 Hz, Δν_(AB)=29.9 Hz), 4.39 (t, 1H,J=5.2 Hz), 3.99–3.61 (m, 6H), 3.91 (s, 3H), 1.62 (d, 3H, J=7.2 Hz); LRMS(APIMS) m/z 462 (M+1)⁺.

Example 27(2S)-2,3-Bis(nitrooxy)propyl(2S)-2-(6-methoxy-5-nitro(2-naphthyl))propanoate and(2S)-2-Hydroxy-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate27a.((4R)-2,2,4-Trimethyl-1,3-dioxolan-4-yl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,32.2 g, 0.14 mol) and((4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)methan-1-ol (15 g, 0.113 mol) inanhydrous dichloromethane (750 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC) (23 g,0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredat room temperature overnight, then quenched with water. The organiclayer was washed with brine, dried over sodium sulfate, filtered, andsolvent was evaporated under reduced pressure. The product was purifiedby column chromatography over silica gel eluting with 20% ethyl acetatein hexane to give the title compound (37.5 g, 96.5% yield) as a whitesolid, mp 65–66° C. ¹H NMR (CDCl₃) δ 7.75 (d, J=8.7 Hz, 1H), 7.73 (d,J=1.2 Hz, 1H), 7.46 (dd, J=8.4 and 1.7 Hz, 1H), 7.15 (m, 2H), 4.27 (m,1H), 4.19 (m, 2H), 4.03–3.92 (m, 2H), 3.96 (s, H), 3.69 (dd, J=8.4 and6.0 Hz, 1H), 1.64 (d, J=7.1 Hz, 3H), 1.40 (s, 3H), 1.37 (s, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.8, 127.1,126.1, 125.9, 119.0, 109.7, 105.5, 73.4, 66.2, 64.8, 55.2, 45.2, 26.5,25.3, 18.4; LRMS (APIMS) m/z 362 (M+NH₄)⁺.

27b.(2R)-2,3-Dihydroxy-2-methylpropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of the product of Example 27a (25 g, 72.6 mmol) intetrahydrofuran (250 mL), water (25 mL), and trifluoroacetic acid (2.5mL) was refluxed for 24 hours. The reaction mixture was cooled to roomtemperature and the solvent was removed. The residue was dissolved indichloromethane, dried over sodium sulfate, filtered, and evaporated invacuo. The product was purified by column chromatography over silica geleluting with ethyl acetate:hexane (50:50) to give the title compound(19.5 g, 89% yield) as a white solid. Mp 65–66° C. ¹H NMR (CDCl₃) δ 7.75(m, 3H), 7.42 (dd, J=8.4 and 1.2 Hz, 1H), 7.2–7.1 (m, 2H), 4.15 (d,J=6.5 Hz, 2H), 3.96 (s, 3H), 3.9 (m, 1H), 3.82 (m, 1H), 3.56 (dd, J=11.5and 4.7 Hz, 1H), 3.44 (dd, J=11.5 and 4.8 Hz, 1H), 2.85 (br s, 2H), 1.61(d, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 175.1, 157.6, 135.2, 133.6,129.2, 128.8, 127.2, 125.94, 125.9, 119.1, 105.5, 69.9, 65.4, 63.1,55.2, 45.3, 18.3; LRMS (APIMS) m/z 322 (M+NH₄)⁺.

27c.(2S)-2,3-Bis(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate and(2S)-2-Hydroxy-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate)

Acetic anhydride (3.1 mL) was added to fuming nitric acid (90%, 0.9 mL)at 0° C. This mixture was then added to a solution of the product ofExample 27b (1.84 g, 6.05 mmol) in anhydrous ethyl acetate (40 mL) at 0C. The reaction mixture was stirred at 0° C. for 45 minutes, treatedwith ice cold water and extracted with ethyl acetate. The combinedorganic extracts were washed with water, brine, dried over sodiumsulfate, and solvent was evaporated to give the crude product that waspurified by flash column chromatography on silica gel eluting withEtOAc:hexane (1:9). The less polar product (2S)-2,3bis(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate was obtained as a white solid(480 mg, 20% yield). Mp 55–57° C. ¹H NMR (CDCl₃) δ 7.76 (d, J=6.8 Hz,2H), 7.7 (s, 1H), 7.42 (d, J=6.5 Hz, 1H), 7.23–7.17 (m, 2H), 5.41 (s,1H), 4.8–4.2 (m, 4H), 3.97 (s, 3H), 3.93 (m, 1H), 1.66 (d, J=6.9 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ 173.8, 157.8, 134.6, 133.8, 129.2, 128.8,127.4, 126.0, 125.8, 119.3, 105.5, 76.1, 66.4, 60.4, 55.3, 45.1, 18.0;LRMS (APIMS) m/z 395 (MH)⁺. The more polar product(2S)-2-hydroxy-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate) was isolated as a white solid(1.1 g, 53% yield). Mp 50–53° C. ¹H NMR (CDCl₃) δ 7.77 (d, J=3.7 Hz,1H), 7.74 (d, J=4.0 Hz, 1H), 7.71 (s, 1H), 7.43 (dd, J=8.4 and 1.4 Hz,1H), 7.21 (dd, J=9.0 and 2.5 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 4.41–4.32(m, 2H), 4.21–4.1 (m, 2H), 4.05 (m, 1H), 3.96 (s, 3H), 3.95 (m, 1H),3.20 (br s, 1H, OH), 1.64 (d, J=7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ174.7, 157.7, 135.0, 133.7, 129.2, 128.85, 127.3, 125.94, 125.9, 119.2,105.6, 72.9, 66.5, 64.8, 55.3, 45.2, 18.2; LRMS (APIMS) m/z 350 (MH)⁺.

Example 28(2R)-2-hydroxy-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate28a. ((4R)-2,2,4-Trimethyl-1,3-dioxolan-4-yl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,33.5 g, 0.145 mol) and ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol(15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC, 23 g,0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredat room temperature overnight, then quenched with water. The organiclayer was washed with brine, dried over sodium sulfate, filtered, andsolvent evaporated under reduced temperature. The product was purifiedby column chromatography on silica gel eluting with EtOAc:hexane (2:8)to give the title compound (35.8 g, 92% yield) as a white solid. Mp79–80° C. ¹H NMR (CDCl₃) δ 7.76 (d, J=9.1 Hz, 2H), 7.46 (dd, J=8.7, 1.8Hz, 1H), 7.19 (m, 2H), 7.0 (s, 1H), 4.28 (m, 1H), 4.18 (m, 2H), 4.0 (n,2H), 3.94 (3H), 3.68 (m, 1H), 1.65 (d, J=7.1 Hz, 3H), 1.41 (s, 3H), 1.38(s, 3H); ¹³C NMR (75 MHz, CDCl₃)δ 174.4, 157.6, 135.3, 133.7, 129.2,128.9, 127.1, 126.1, 126.0, 119.0, 109.6, 105.5, 73.4, 66.1, 64.4, 55.2,45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 345 (MH).

28b.(2R)-2,3-Dihydroxy-2-methylpropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of the product of Example 28a (38 g, 110 mmol) intetrahydrofuran (360 mL), water (40 mL) and trifluoroacetic acid (4 mL)was refluxed for 24 hours. The reaction mixture was cooled to roomtemperature and solvent was evaporated. The residue was dissolved indichloromethane, dried over sodium sulfate, filtered, and solvent wasevaporated. The product was purified by column chromatography on silicagel eluting with EtOAc:hexane (1:1) to give the title compound (27.5 g,81% yield) as a white solid. Mp 65–71° C. ¹H NMR (CDCl₃) δ 7.75 (dd,J=8.3, 1.5 Hz, 2H), 7.70 (s, 1H), 7.41 (dd, J=8.5, 1.7 Hz, 1H), 7.18 (m,2H), 4.17 (dd, J=6.2 and 3.5 Hz, 2H), 3.96 (s, 3H), 3.95–3.84 (m, 2H),3.60 (m, 1H), 3.49 (m, 1H), 2.51 (br s, 2H, 2×OH), 1.62 (d, J=7.2 Hz,3H); ¹³C NMR (75 MHz, CDCl₃) δ 175.1, 157.7, 135.2, 133.7, 129.2, 128.8,127.26, 125.93, 125.9, 119.1, 105.5, 70.0, 65.4, 63.1, 55.3, 45.3, 18.3;LRMS (APIMS) m/z 305 (MH)⁺, 322 (M+NH₄)⁺.

28c.(2R)-2-Hydroxy-3-(nitrooxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

The product of Example 28b was nitrated following the procedure forExample 27d to give a mixture of the product of Example 5 (29% yield)and the title compound (34% yield) as white solids. ¹H NMR (CDCl₃) δ7.78 (d, J=3.4 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.71 (s, 1H), 7.42 (dd,J=7.5 and 1.5 Hz, 1H), 7.21 (dd, J=8.8 and 2.4 Hz, 1H), 7.17 (d, J=2.3Hz, 1H), 4.4 (m, 2H), 4.3–4.1 (m, 3H), 3.96 (s, 3H), 3.95 (m, 1H), 3.20(br s, 1H, OH), 1.65 (d, J=7.1 Hz, 3H); LRMS (APIMS) m/z 350 (MH)⁺.

Example 29(2S)-2-(6-Methoxy(2-naphthyl))-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methoxy)propanamide29a. tert-Butyl 2-(1,3-dioxobenzo(c)azolin-2-yloxy)acetate

A mixture of N-hydroxyphthalimide (10 g, 61.3 mmol), K₂CO₃ (16.9 g, 122mmol) and tert-butyl bromoacetate (12 g, 9 mL, 61.3 mmol) in DMF (60 mL)was stirred at room temperature for 3 hours and the solvent wasevaporated under high vacuum. The residue was dissolved in EtOAc, washedwith brine, dried over Na₂SO₄ and filtered. The residue afterevaporation of the solvent was recrystallized from a mixture ofCH₂Cl₂/EtOAc/hexane to give the title compound (12 g, 71% yield) as awhite solid. Mp 140–141° C. ¹H NMR (300 MHz, CDCl₃) δ 7.80–7.90 (m, 2H),7.74–7.77 (m, 2H), 4.71 (s, 2H), 1.49 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ166.0, 163.0, 134.7, 128.9, 123.7, 83.0, 73.5, 28.1. Mass spectrum(API-TIS) m/z 278 (MH⁺), 295 (MNH₄ ⁺). Anal. calcd. for C₁₄H₁₅NO₅: C,60.64; H, 5.45; N, 5.05. Found: C, 60.47; H, 5.31; N, 4.96.

29b. tert-Butyl 2-aminooxyacetate

Hydrazine monohydrate (2.1 g, 2.1 mL, 67.3 mmol) was added drop-wise toa solution of the product of Example 29a (4.65 g, 16.8 mmol) in CH₂Cl₂(25 mL) and methanol (3 mL) at room temperature. The resultantsuspension was stirred at room temperature for 30 minutes. The residue,after evaporation of the solvent, was dissolved in 5% Na₂CO₃ andextracted with EtOAc. The organic layer was washed with water, brine,dried over anhydrous Na₂SO₄, filtered and evaporated in vacuo to givethe title compound (2.36 g, 96% yield) as a colorless oil. ¹H NMR (300MHz, CDCl₃) δ 5.80–5.90 (bs, 2H), 4.13 (s, 2H), 1.50 (s, 9H). Massspectrum (API-TIS) m/z 148 (MH⁺).

29c. tert-Butyl2-((2S)-2-(6-methoxy(2-naphthyl))propanoylaminooxy)acetate

A mixture of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 1.6g, 7.0 mmol), the product of Example 29b (1 g, 7.0 mmol) andN,N-dimethylaminopyridine ((DMAP, 0.85 g, 7.0 mmol) in CH₂Cl₂ (20 mL) at0° C. was treated with 1-(3-(dimethylamino)propyl)-3-ethylcarbodimidehydrochloride (1.34 g, 7.0 mmol). The reaction mixture was stirred atroom temperature for 3 days, diluted with CH₂Cl₂, washed with water,brine and dried over Na₂SO₄. The residue after filtration andevaporation was chromatographed on silica gel eluting with EtOAc:hexane(1:3 to 1:2) to give the title compound (1.9 g, 74% yield) as a whitesolid. Mp 82–84° C. ¹H NMR (300 MHz, CDCl₃) δ 8.72–8.85 (bs, 1H),7.63–7.70 (m, 3H), 7.34 (dd, J=1.6 and 8.5 Hz, 1H), 7.02–7.16 (m, 2H),4.15–4.37 (bs, 2H), 3.89 (s, 3H), 3.49–3.64 (bs, 1H), 1.56 (d, J=7.0 Hz,3H), 1.30 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 171.9, 168.8, 157.8, 135.4,133.8, 129.3, 129.0, 127.5, 126.0, 119.2, 105.6, 82.7, 72.5, 55.3, 44.0,27.9, 18.3. Mass spectrum (API-TIS) m/z 360 (MH⁺). Anal. calcd. forC₂₀H₂₅NO₅: C, 66.84; H, 7.01; N, 3.90. Found: C, 66.85; H, 6.99; N,3.84.

29d. 2-((2S)-2-(6-Methoxy(2-naphthyl))propanoylaminooxy)acetic acid

Trifluoroacetic acid (4 mL) was added drop-wise to a solution of theproduct of Example 29c (1.8 g, 5.0 mmol) in CH₂Cl₂ (8 mL). The reactionmixture was stirred at room temperature for 16 hours and the volatilematerial removed in vacuo. The residue after evaporation wasrecrystallized from EtOAc/hexane to give the title compound (1.32 g, 87%yield) as a white solid. Mp 152–153° C. ¹H NMR (300 MHz, d₆-DMSO) δ8.98–9.10 (bs, 1H), 7.60–7.90 (m, 3H), 7.42 (dd, J=1.5 and 8.7 Hz, 1H),7.25–7.29 (m, 1H), 7.15 (dd, J=2.7 and 9.0 Hz, 1H), 4.32 (ABq,J_(AB)=16.9 Hz, Δν_(AB)=23.7 Hz, 2H), 3.86 (s, 3H), 3.64 (q, J=7.8 Hz,1H), 1.40 (d, J=7.0 Hz, 3H). ¹³C NMR (75 MHz, d₆-DMSO) δ 171.0, 170.3,157.1, 136.3, 133.2, 129.2, 128.4, 126.7, 126.3, 125.4, 118.7, 105.7,71.6, 55.2, 41.5, 18.1. Mass spectrum (API-TIS) m/z 304 (MH⁺). Anal.calcd. for C₁₆H₁₇NO₅: C, 63.36; H, 5.65; N, 4.62. Found: C, 63.42; H,5.44; N, 4.42.

29e.(2S)-2-(6-Methoxy(2-naphthyl))-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methoxy)propanamide

A mixture of the product of Example 29d (0.5 g, 1.65 mmol), the productof Example 22a (0.28 g, 1.65 mmol) and N,N-dimethylaminopyridine (DMAP,0.20 g, 1.65 mmol) in CH₂Cl₂ (5 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.35 g,1.65 mmol) in CH₂Cl₂ (5 mL). The reaction mixture was stirred at 0° C.for 3 hours, diluted with CH₂Cl₂, washed with water, brine and driedover Na₂SO₄. The residue after filtration and evaporation waschromatographed on silica gel eluting with EtOAc:hexane (1:2) toMeOH:EtOAc:hexane (0.1:1:1) to give the title compound (0.33 g, 51%yield) as a white solid. Mp 40–44° C. ¹H NMR (300 MHz, CDCl₃) δ8.79–8.90 (bs, 1H), 8.48–8.51 (bs, 1H), 7.60–7.76 (m, 3H), 7.32 (dd,J=1.7 and 8.4 Hz, 1H), 7.11–7.20 (m, 2H), 4.54 (t, J=5.0 Hz, 2H), 4.23(s, 2H), 3.92 (s, 3H), 3.59–3.67 (m, 3H), 1.59 (d, J=7.1 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ 175.1, 169.4, 158.1, 134.5, 134.1, 129.3, 129.0,127.9, 126.3, 125.8, 119.6, 105.7, 76.0, 71.1, 55.5, 44.0, 36.6, 18.2.Mass spectrum (API-TIS) m/z 392 (MH⁺). Anal. calcd. for C₁₈H₂₁N₃O₇: C,55.24; H, 5.41; N, 10.74. Found: C, 54.97; H, 5.42; N, 10.52.

Example 30 3-(2-(4-((Nitrooxy)methyl)phenyl)acetyloxy)-2-oxopropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate 30a.2-(4-((Nitrooxy)methyl)phenyl)acetic acid

A solution of silver nitrate (7.78 g, 45.8 mmol) and4-(bromomethyl)phenylacetic acid (5.18 g, 22.6 mmol) in THF (100 mL) andacetonitrile (50 mL) was stirred at ambient temperature overnight andthen at 50° C. for 1 hour. The reaction mixture was then cooled toambient temperature and stirred with brine (100 mL) for 1 hour. Theresulted mixture was filtered through Celite and washed with water. Thefiltrate was concentrated and then extracted with ethyl acetate. Thecombined organic extracts were washed with water, brine, dried overNa₂SO₄, filtered concentrated and dried under vacuum. The product waspurified by silica gel column chromatography eluting with EtOAc/hexane(2:3, Rf=0.13) to obtained the title compound as a white solid (3.2 g,67% yield). Mp 109–110° C. ¹H NMR (300 MHz, d₄-methanol) δ 8.23 (d,J=8.0 Hz, 2H), 8.14 (d, J=8.0 Hz, 2H), 6.34 (s, 2H), 4.43 (s, 2H). ¹³CNMR (75 MHz, d₄-methanol) δ 172.6, 136.5, 130.7, 129.9, 129.5, 75.1,40.5. Mass spectrum (API-TIS) m/z 210 (M−H)⁻.

30b.3-(2-(4-((Nitrooxy)methyl)phenyl)acetyloxy)-2-oxopropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

1,3-Dicyclohexylcarbodiimide (1.55 g, 7.5 mmol) was added to a solutionof the product of Example 11b (2.13 g, 7.1 mmol), the product of Example30a (1.49 g, 7.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.93 g, 7.6mmol) in CH₂Cl₂ (100 mL) and stirred at ambient temperature overnight.The byproduct, dicyclohexyl urea, was removed by filtration. Thefiltrate was concentrated and the residue was dissolved in CH₂Cl₂ (150mL), washed with 3N HCl (100 mL), water (100 mL), brine, and dried overNa₂SO₄, filtered and concentrated. The product was purified by silicagel column chromatography eluting with EtOAc/hexane (1:2, Rf=0.15) toobtained the title compound as a oil (1.25 g, 36% yield). The oilsolidified after standing for 3 months at ambient temperature. Mp 92–95°C. ¹H NMR (300 MHz, CDCl₃) δ 7.7–7.1 (m, 10H), 5.35 (s, 2H), 4.7–4.6 (m,4H), 3.95 (q, J=7.1 Hz, 1H), 3.89 (s, 3H), 3.69 (s, 2H), 1.59 (d, J=7.1Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 197.5, 173.7, 170.2, 157.7, 134.7,134.6, 133.7, 131.2, 129.8, 129.3, 129.2, 128.8, 127.2, 126.03, 126.0,119.1, 105.5, 74.3, 66.4, 55.2, 44.9, 40.2, 18.3. Mass spectrum(API-TIS) m/z 496 (MH)⁺.

Example 31 2-(4-(2-(nitrooxy)ethyl)piperidyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate 31a.Nitrooxy(2-(4-piperidyl)ethyl)hydrogennitrate

4-Piperidylethan-1-ol (10 g, 77.3 mmol) in a mixture of EtOAc (90 mL)and CH₂Cl₂ (5 mL) was added drop-wise to a mixture of fuming HNO₃ (24.4g, 16.3 mL, 387 mmol) and Ac₂O (63.2 g, 58.4 mL, 619 mmol) at −10° C.The reaction mixture was stirred at −10° C. for 30 minutes and thendiluted with EtOAc and hexane. The precipitate was collected byfiltration and washed with hexane to give the title compound (7.5 g, 41%yield) as a white solid. Mp 86–88° C. ¹H NMR (300 MHz, d₆-DMSO)δ8.20–8.30 (bs, 1H, 8.05–8.20 (bs, 1H), 4.57 (t, J=6.2 Hz, 2H), 3.15–3.30(m, 2H), 2.70–2.90 (m, 2H), 1.75–1.90 (m, 2H), 1.55–1.72 (m, 3H),1.19–1.37 (m, 2H). ¹³C NMR (75 MHz, d₆-DMSO) δ 71.6, 43.2, 31.9, 30.0,28.1. Mass spectrum (API-TIS) m/z 175 (MH⁺). Anal. calcd. for C₇H₁₅N₃O₆:C, 35.44; H, 6.37; N, 17.71. Found: C, 35.62; H, 6.39; N, 17.65.

31b.2-(4-(2-(Nitrooxy)ethyl)piperidyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of the product of Example 17b (1.5 g, 5.21 mmol), the productof Example 31a (1.2 g, 5.21 mmol) and N,N-dimethylaminopyridine (DMAP,0.63 g, 5.21 mmol) in CH₂Cl₂ (30 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (1.0 g,5.21 mmol). The reaction mixture was stirred at 0° C. for 3 hours,diluted with CH₂Cl₂, washed with water, brine and dried over Na₂SO₄. Theresidue after filtration and evaporation was chromatographed on silicagel eluting with EtOAc:Hexane (1:3 to 1:2 to 1:1) to give the titlecompound (1.0 g, 43% yield) as a white solid. Mp 83–85° C. ¹H NMR (300MHz, d₆-DMSO) δ 7.65–7.75 (m, 3H), 7.44 (d, J=8.5 Hz, 1H), 7.07–7.18 (m,2H), 4.46–4.81 (m, 3H), 4.30–4.44 (m, 2H), 3.99 (q, J=6.9 Hz, 1H), 3.91(s, 3H), 3.50–3.59 (m, 1H), 2.75–2.93 (m, 1H), 2.41–2.60 (m, 1H), 1.63(d, J=7.9 Hz, 3H), 1.32–1.74 (m, 5H), 0.69–1.20 (m, 2H). ¹³C NMR (75MHz, d₆-DMSO) δ 174.3, 164.8, 157.8, 135.5, 133.9, 129.4, 129.0, 127.3,126.5, 126.4, 119.1, 105.7, 70.7, 62.3, 55.4, 45.4, 44.8, 42.2, 33.0,32.6, 32.0, 31.4, 18.4. Mass spectrum (API-TIS) m/z 445 (MH⁺), 462 (MNH₄⁺). Anal. calcd. for C₂₃H₂₈N₂O₇: C, 62.15; H, 6.35; N, 6.30. Found: C,62.21; H, 6.42; N, 6.26.

Example 324-((2-(Nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl))propanoate32a. 2-(Nitrooxy)ethyl 4-hydroxybenzoate

To 4-hydroxybenzoic acid (1.2918 g, 9.347 mmol) in DMF (10 mL) was addedpotassium carbonate (1.60 g, 11.6 mmol) and the product of Example 15a(1.44 g, 8.48 mmol). The reaction mixture was stirred at roomtemperature for 48 hours, filtered, and concentrated to dryness. Theproduct was dissolved in EtOAc, washed with H₂O, brine, dried overmagnesium sulfate, filtered, and concentrated. The product waschromatographed on silica gel eluting with MeOH:CH₂Cl₂ (0:100, then2:98) to give the title compound (430.2 mg, 22% yield). ¹H NMR (300 MHz,CDCl₃) δ 7.95 (d, J=7.4 Hz, 2H), 6.89 (d, J=7.4 Hz, 2H), 6.24 (s, 1H),4.80 (m, 2H), 4.59 (m, 2H). ¹³C NMR (75 MHz, CDCl₃)δ 166.1, 160.5,132.2, 121.5, 115.4, 70.6, 60.6. Mass spectrum APIMS (IS, NH₄OAc) m/z228 (M+H⁺), 245 (M+NH₄ ⁺), 250 (M+Na⁺).

32b. 4-((2-(Nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 456.0 mg,1.980 mmol) and the product of Example 32a (399.1 mg, 1.757 mmol) inCH₂Cl₂ (20 mL) was added N,N-dicyclohexylcarbodiimide (418.4 mg, 2.028mmol). The reaction mixture was stirred for 15 minutes and thenN,N-dimethylaminopyridine (185.0 mg, 1.51 mmol) was added. The reactionmixture was stirred at room temperature for 3 hours and filtered toremove the solid. The solid was washed with dichloromethane. Thefiltrate was washed with citric acid (0.2 M), brine, sodium bicarbonatesolution, brine, dried over magnesium sulfate, filtered, andconcentrated. The product was chromatographed on silica gel eluting withCH₂Cl₂ to give the title compound (0.62 g, 81% yield). ¹H NMR (300 MHz,CDCl₃) δ 8.03–7.98 (m, 2H), 7.77–7.72 (m, 3H), 7.49 (dd, J=8.6 Hz & 1.7Hz, 1H), 7.19–7.14 (m, 2H), 7.10–7.06 (m, 2H), 4.78–4.75 (m, 2H),4.58–4.55 (m, 2H), 4.11 (q, J=7.1 Hz, 1H), 3.92 (s, 3H), 1.70 (d, J=7.1Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 172.6, 165.3, 157.8, 154.9, 134.7,133.9, 131.3, 129.3, 128.9, 127.5, 126.7, 126.2, 125.9, 121.6, 119.2,105.6, 70.4, 60.8, 55.3, 45.6, 18.4. Mass spectrum APIMS (IS, NH₄OAc)m/z 440 (M+H⁺), 457 (M+NH₄ ⁺), 462 (M+Na⁺), 896 (2M+NH₄ ⁺).

Example 332-((2-(Nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate33a. 2-(Nitrooxy)ethyl2-hydroxybenzoate

To the product of Example 15a (1.80 g, 10.6 mmol) inN,N-dimethylfromamide (10 mL) was added salicylic acid (1.4620 g, 10.6mmol) and potassium carbonate (1.4827 g, 10.7 mmol). The reactionmixture was stirred at room temperature for two hours then at 65° C.overnight, and concentrated to dryness. The product was treated withEtOAc and filtered. The filtrate was washed with sodium bicarbonate,brine, dried over magnesium sulfate, filtered, and concentrated. Theproduct was chromatographed on silica gel eluting with EtOAc:hexane(3:97, 1:9, 1:5, 2:3) to give the title compound (0.35 g, 14% yield). ¹HNMR (300 MHz, CDCl₃) δ 10.5 (s, 1H), 7.84–7.81 (m, 1H), 7.51–7.45 (m,1H), 7.00–6.97 (m, 1H), 6.92–6.87 (m, 1H), 4.86–4.79 (m, 2H), 4.64–4.61(m, 2H). ¹³C NMR (75 MHz, CDCl₃)δ 169.6, 161.7, 136.3, 129.9, 119.4,117.7, 111.6, 70.1, 60.9.

33b. 2-((2-(nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate

To a mixture of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,324.5 mg, 1.409 mmol), the product of Example 33a (292.6 mg, 1.288mmol), and N,N-dicyclohexylcarbodiimide (153.2 mg, 1.254 mmol) was addedCH₂Cl₂ (15 mL) and N,N-dimehtylaminopyridine (284.4 mg, 1.378 mmol). Thereaction mixture was stirred at room temperature for 3 hours, andfiltered. The filtrate was washed with citric acid (0.2 M), brine,sodium bicarbonate solution, brine, dried over magnesium sulfate,filtered, and concentrated. The product was chromatographed on silicagel eluting with CH₂Cl₂ to give the title compound (355.8 mg, 63%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.96–7.94 (m, 1H), 7.79–7.72 (m, 3H),7.54–7.46 (m, 2H), 7.29–7.24 (m, 1H), 7.17–7.14 (m, 2H), 6.93–6.91 (m,1H), 4.60–4.57 (m, 2H), 4.43–4.30 (m, 2H), 4.19 (q, J=7.1 Hz, 1H), 3.91(s, 3H), 1.72 (d, J=7.1 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 173.1, 164.0,157.7, 150.7, 135.0, 134.1, 133.8, 131.6, 129.3, 128.9, 127.2, 126.34,126.31, 126.0, 123.6, 122.7, 119.1, 105.5, 70.3, 60.6, 55.3, 45.4, 18.6.Mass spectrum APIMS (IS, NH₄OAc) m/z 440 (M+H⁺), 457 (M+NH₄ ⁺), 462(M+Na⁺), 896 (2M+NH₄ ⁺).

Example 34(N-methyl-N-(3-(nitrooxy)propyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate34a. N-(3-Hydroxypropyl)carboxamide

3-Amino-1-propanol (10.0 mL, 130.7 mmol) and ethyl formate (31.7 mL,392.2 mmol) were combined together and stirred at room temperature for24 hours. The excess ethyl formate was removed under reduced pressure togive the title compound (8.6 g, 64% yield) as a yellow oil. ¹H NMR (300MHz, CDCl₃); δ 8.11–8.04 (m, 1H), 3.63–3.61 (m, 2H), 3.37–3.33(m, 2H),1.87–1.85 (m, 2H).

34b. 3-(Methylamino)propan-1-ol

A solution of the product of Example 34a (8.60 g, 83.3 mmol) in 10 mL ofTHF was added to LAH in THF (1M, 100 mL) at 0° C. The mixture was heatedreflux for 3 hours. Water was added (3.79 mL) followed by NaOH solution(10%, 11.4 mL) and water (3.79 mL). The resulting solid was removed viafiltration and the solid washed with additional THF (10 mL). Thefiltrate was collected and the solvent removed under reduced pressure togive the title compound (4.40 g, 59% yield) as a yellow oil which wasused without further purification. ¹H NMR (300 MHz, CDCl₃); δ 3.74 (m2H), 2.78 (m, 2H), 2.38 (s, 3H), 1.66 (q, J=5.0, 2H).

34c. Methyl(3-(nitrooxy)propyl)amine

The product of Example 34b (750.0 mg, 4.28 mmol) dissolved in EtOH wascooled to 0° C. One equivalent of fuming nitric acid (90%, 199.8 μL,4.28 mmol) was added and the mixture stirred for 15 minutes. Theresulting solution was added drop-wise to a mixture of fuming nitricacid (90%, 300 μL, 6.42 mmol) and acetic anhydride (913 μL, 9.84 mmol)at 0° C. and the solution mixture stirred for 3 hours The excess solventwas removed under reduced pressure. Ether was added and the samplesonicated for 15 minutes. The excess ether was decanted off and thesample dried under vacuum overnight to give a yellow oil (1.29 g) thatwas used without further purification. ¹H NMR (300 MHz, CDCl₃); δ4.60–4.56 (m, 2H), 3.23–3.16 9M, 2H), 2.80 (br s, 3H), 2.28–2.19 (m,2H).

34d.(N-methyl-N-(3-(nitrooxy)propyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of EDC (1.10 g, 5.77 mmol) in CH₂Cl₂ (7 mL) was addeddrop-wise to a mixture of the product of Example 17b (1.38 g, 4.81 mmol)and the product of Example 34c (1.29 g, 9.61 mmol) in CH₂Cl₂ (5 mL). Themixture was stirred at room temperature for 5 hours. Water was added (15mL) and the organic phase separated. The water layer was extracted withadditional CH₂Cl₂ and the combined organic extracts were dried overMgSO₄, and evaporated to give a yellow oil (1.96 g). The oil waschromatographed on silica gel plug eluting with hexanes/EtOAc (3:1) andthe eluant concentrated and dried under vacuum overnight. The resultingsolid was trituration in Et₂O followed by recrystallization fromCH₂Cl₂hexanes to give the title compound as a white solid (535.5 mg, 28%yield). Mp 104–105° C. ¹H NMR (300 MHz, CDCl₃); δ 7.72 (br s, 1H), 7.69(br s, 2H), 7.44 (dd, J=8.6, 1.5 Hz, 1H,), 7.11–7.15 (m, 2H), 4.76 (d,J=14.4 Hz, 1H), 4.57 (d, J=14.4 Hz, 1H), 4.44 (t, J=6.4 Hz, 2H), 4.01(q, J=7.2 Hz, 1H), 3.91 (s, 3H), 3.46 (dt, J=2.7, 6.9 Hz, 2H), 2.89 (s,3H), 1.95 (q, J=6.7 Hz, 2H), 1.63 (d, 3H, J=7.2). Mass spectrum(API-TIS) m/z 405 (M+1).

Example 35(2S)-2-(6-Methoxy(2-naphthyl))-N-(2-(4-((nitrooxy)methyl)piperidyl)-2-oxoethoxy)propanamide35a.(2S)-2-(6-Methoxy(2-naphthyl))-N-(2-(4-((nitrooxy)methyl)piperidyl)-2-oxoethoxy)propanamide

A mixture of the product of Example 29d (1 g, 3.33 mmol), the product ofExample 19a (0.73 g, 3.33 mmol) and N,N-dimethylaminopyridine (DMAP,0.40 g, 3.33 mmol) in CH₂Cl₂ (10 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.70 g,3.63 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at 0° C.for 3 hours, diluted with CH₂Cl₂, washed with water, brine and driedover Na₂SO₄. The residue after filtration and evaporation waschromatographed on silica gel eluting with EtOAc:hexane (1:2) toMeOH:EtOAc:hexane (0.1:1:1) to give the title compound (0.93 g, 63%yield) as a white foam solid. Mp 45–47° C. ¹H NMR (300 MHz, CDCl₃) δ8.70–8.80 (bs, 1H), 7.62–7.71 (m, 3H), 7.36–7.43 (m, 1H), 7.06–7.17 (m,2H), 4.35–4.51 (m, 3H), 4.20–4.30 (m, 1H), 4.02–4.16 (m, 1H), 3.90 (s,3H), 3.40–3.62 (m, 2H), 2.71–2.95 (m, 1H), 2.32–2.55 (m, 1H), 1.80–2.00(m, 1H), 1.60–1.80 (m, 2H), 1.57 (d, J=7.0 Hz, 3H), 1.02–1.20 (m, 1H),0.80–1.00 (m, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 166.6, 157.7, 135.8, 133.7,129.3, 128.9, 127.3, 126.2, 125.9, 119.1, 105.5, 72.7, 72.5, 55.4, 44.0,43.6, 41.2, 34.1, 28.7, 28.0, 18.5. Mass spectrum (API-TIS) m/z 446(MH⁺). Anal. calcd. for C₂₂H₂₇N₃O₇: C, 59.32; H, 6.11; N, 9.43. Found:C, 59.54; H, 6.20; N, 9.55.

Example 363-((2-(Nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate36a. 2-(Nitrooxy)ethyl 3-hydroxybenzoate

To the product of Example 15a (2.1042 g, 12.380 mmol) and3-hydroxybenzoic acid (1.95 g, 14.12 mmol) in DMF (10 mL) was addedpotassium carbonate (1.98 g, 14.33 mmol). The reaction mixture wasstirred at room temperature overnight, and filtered. The filtrate wasconcentrated to dryness, dissolved in EtOAc, washed with water, sodiumbicarbonate solution, brine, dried over magnesium sulfate, filtered, andconcentrated. The product was chromatographed on silica gel eluting withMeOH:CH₂Cl₂ (0:100, 2:98, 3:97) to give the title compound (1.51 g, 53%yield). ¹H NMR (CDCl₃) δ 7.60–7.54 (m, 2H), 7.34–7.26 (m, 1H), 7.12–7.08(m, 1H), 6.60 (s, 1H), 4.79–4.77 (m, 2H), 4.60–4.57 (m, 2H). ¹³C NMR(CDCl₃) δ 8166.6, 155.9, 130.2, 129.9, 122.0, 120.9, 116.3, 70.3, 61.1.Mass spectrum APIMS (IS, NH₄OAc) m/z 245 (M+NH₄ ⁺), 250 (M+Na⁺), 472(2M+NH₄ ⁺).

36b. 3-((2-(Nitrooxy)ethyl)oxycarbonyl)phenyl(2S)-2-(6-methoxy(2-naphthyl)propanoate

To a mixture of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,1.67 g, 7.25 mmol), the product of Example 36a (1.4492 g, 6.379 mmol),and N,N-dimethylaminopyridine (DMAP, 752.7 mg, 6.161 mmol) in CH₂Cl₂ (40mL) was added N,N-dicyclohexylcarbodiimide (1.61 g, 7.80 mmol). Thereaction mixture was stirred at room temperature overnight, andfiltered. The filtrate was diluted with CH₂Cl₂, washed with citric acid(0.2M), brine, sodium bicarbonate solution, brine, dried over magnesiumsulfate, filtered, and concentrated. The product was chromatoghraphed onsilica gel eluting with CH₂Cl₂ to give the title compound (2.3² g, 83%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.89–7.86 (m, 1H), 7.79–7.73 (n, 3H),7.67–7.66 (m, 1H), 7.52–7.48 (m, 1H), 7.44–7.38 (m, 1H), 7.26–7.15 (m,3H), 4.78–4.75 (m, 2H), 4.59–4.56 (m, 2H), 4.12 (q, J=7.1 Hz, 1H), 3.92(s, 3H), 1.71 (d, J=7.1 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃)δ 172.9, 165.1,157.7, 150.8, 134.8, 133.8, 130.6, 129.4, 129.3, 128.9, 127.4, 127.1,126.7, 126.1, 125.9, 122.8, 119.1, 105.5, 70.3, 60.9, 55.3, 45.5, 18.4.Mass spectrum APIMS (IS, NH₄OAc) m/z 440 (M+H⁺), 457 (M+NH₄ ⁺), 462(M+Na⁺), 896 (2M+NH₄ ⁺).

Example 37 2-(4-(2-(Nitrooxy)ethyl)piperazinyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate hydrogen chloride 37a.Nitrooxy(2-piperazinylethyl)dihydrogennitrate

2-Piperazinylethan-1-ol (15 g, 115 mmol) in a mixture of EtOAc (132 mL)and CH₂Cl₂ (5 mL) was added drop-wise to a mixture of fuming HNO₃ (36.3g, 24.2 mL, 576 mmol) and Ac₂O (94.1 g, 87 mL, 921 mmol) at −10° C. Thereaction mixture was stirred at −10° C. for 30 minutes and diluted withEtOAc and hexane. The oil was separated and dried under vacuum to givethe title compound (5.1 g, 19% yield) as a sticky oil. The crude productwas used without further purification. Mass spectrum (API-TIS) m/z 176(MH⁺).

37b.2-(4-(2-(Nitrooxy)ethyl)piperazinyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of the product of Example 17b (2.67 g, 9.27 mmol), the productof Example 37a (2.2 g, 9.27 mmol) and N,N-dimethylaminopyridine (DMAP,3.39 g, 27.8 mmol) in CH₂Cl₂ (20 mL) and DMF (9.3 mL) at 0° C. wastreated with 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimidehydrochloride (1.78 g, 9.27 mmol). The reaction mixture was stirred at0° C. for 3 hours, diluted with CH₂Cl₂, washed with saturated NaHCO₃,dried over Na₂SO₄. The residue after filtration and evaporation waschromatographed on silica gel eluting with MeOH:EtOAc:CH₂Cl₂ (1:25:25)to give the title compound (1.2 g, 29% yield) as an oil. ¹H NMR (300MHz, d₆-DMSO) δ 7.65–7.72 (m, 3H), 7.43 (dd, J=1.6 and 8.5 Hz, 1H),7.07–7.16 (m, 2H), 4.66 (ABq, J_(AB)=14.0 Hz, Δν_(AB)=28.0 Hz, 2H), 4.43(t, J=5.5 Hz, 2H), 3.98 (q, J=7.1 Hz, 1H), 3.89 (s, 3H), 3.46–3.61 (m,2H), 3.14–3.23 (m, 2H), 2.49–2.56 (m, 2H), 2.32–2.44 (m, 2H), 2.12–2.20(m, 2H), 1.63 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, d₆-DMSO) δ 174.2,172.2, 164.9, 157.8, 135.4, 135.8, 129.4, 129.0, 127.3, 126.4, 126.3,119.1, 105.7, 70.1, 62.1, 55.4, 54.8, 52.9, 45.3, 44.6, 41.9, 18.7. Massspectrum (API-TIS) m/z 446 (MH⁺). Anal. calcd. for C₂₂H₂₇N₃O₇: C, 59.32;H, 6.11; N, 9.43. Found: C, 59.11; H, 5.86; N, 9.24.

37c.2-(4-(2-(Nitrooxy)ethyl)piperazinyl)-2-oxoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoatehydrogen chloride

To a solution of the product of Example 37b (0.3 g, 0.67 mmol) in EtOAc(4.3 mL) at 0° C. was added drop-wise a solution of HCl gas in Et₂O (24mg, 0.33 mL, 2M solution, 0.67 mmol). The cloudy solution was dissolvedin excess EtOAc and hexane was added. The solvent was evaporated to asmall volume. The precipitate was filtered, washed with hexane to givethe title compound (0.3 g, 92% yield) as a white solid. Mp 129–131° C.¹H NMR (300 MHz, d₆-DMSO) δ 11.65–12.00 (bs, 1H), 7.73–7.82 (m, 3H),7.44 (dd, J=1.4 and 8.6 Hz, 1H), 7.28–7.32 (m, 1H), 7.16 (dd, J=2.5 and8.9 Hz, 1 H), 4.78–4.97 (m, 4H), 4.22–4.45 (m, 1H), 4.03 (q, J=7.1 Hz,1H), 3.87 (s, 3H), 3.80–4.05 (m, 1H), 3.35–3.67 (m, 5H), 2.90–3.30 (m,3H), 1.52 (d, J=7.1 Hz, 3H). ¹³C NMR (75 MHz, d₆-DMSO) δ 173.5, 165.0,157.2, 135.5, 133.3, 129.1, 128.4, 126.9, 126.5, 125.8, 118.7, 105.7,67.4, 61.4, 55.2, 50.8, 18.7. Mass spectrum (API-TIS) m/z 446 (MH⁺).Anal. calcd. for C₂₂H₂₈ClN₃O₇: C, 54.83; H, 5.86; N, 8.72. Found: C,54.78; H, 5.89; N, 8.65.

Example 383-((2S)-2-(6-Methoxy(2-naphthyl)propanoyloxy)-2-methyl-2-((nitrooxy)methyl)propyl(2S)-2-(6-methoxy(2-naphthyl)propanoate38a.2-(((2S)-2-(6-Methoxy(2-naphthyl)propanoyloxy)methyl)-3-hydroxy-2-methylpropyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a stirred solution of 1,1,1-tris(hydroxymethyl)ethane (1.32 g, 11mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.07 g,22 mmol) and 1,3-dicyclohexylcarbodiimide (4.54 g, 22 mmol) inacetonitrile (100 mL) was added N,N-dimethylaminopyridine (DMAP, 10 mg).The reaction mixture was stirred at ambient temperature for 15 hours,filtered, and the filtrate was concentrated. The crude product waspurified by chromatography on silica gel eluting with EtOAc:hexane (1:1)to give the title compound (4.36 g, 72% yield) as a white solid. Mp 96°C. ¹H NMR (300 MHz, CDCl₃) δ 7.71–7.63 (m, 6H), 7.37–7.33 (m, 2H),7.17–7.10 (m, 4H), 3.99–3.82 (m, 12H), 3.11 (t, J=6.7 Hz, 2H), 2.26 (t,J=6.7 Hz, 1H), 1.58–1.54 (m, 6H), 0.70 (s, 3H). ¹³C NMR (75 MHz, CDCl₃)δ 174.72, 174.66, 157.57, 135.24, 135.20, 133.62, 129.16, 128.77,127.13, 125.97, 125.84, 118.98, 105.49, 66.01, 65.97, 64.35, 55.17,45.35, 40.35, 18.04, 16.45. Mass spectrum (API-TIS) m/z 562.4((M+NH₄)⁺).

38b.3-((2S)-2(6-Methoxy(2-napthyl)propanoyloxy)-2-methyl-2-((nitrooxy)methyl)propyl(2S)-2-(6-methoxy(2-naphthyl)propanoate

Fuming nitric acid (90%, 1.00 mL, 21 mmol) was added drop-wise to aceticanhydride (3 mL) at 0° C. with stirring. After 15 min, a precooledsolution of the product of Example 38a (2.72 g, 5.00 mmol) in THF (30mL) was added. The mixture was stirred at the same temperature for 20minutes, EtOAc added, washed with aqueous NaHCO₃ (2×), dried overNa₂SO₄, filtered, and concentrated. The residue was purified bychromatography on silica gel eluting with EtOAc:hexane (1:2) to give thetitle compound (2.55 g, 87% yield) as a white solid. Mp 88–89° C. ¹H NMR(300 MHz, CDCl₃) δ 7.68–7.59 (m, 6H), 7.31–7.27 (m, 2H), 7.15–7.08 (m,4H), 4.02–3.77 (m, 14H, 1.54 (d, J=2.5 Hz, 3H), 1.51 (d, J=2.5 Hz, 3H),0.74 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 173.88, 173.85, 157.65, 135.09,133.69, 129.18, 128.81, 127.21, 125.91, 125.86, 119.07, 105.53, 65.39,65.24, 55.23, 45.28, 38.69, 17.93, 16.77. Mass spectrum (API-TIS) m/z607.4 ((M+NH₄)⁺).

Example 392-(4-(2-(Nitrooxy)ethoxy)phenoxy)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate39a.2-(4-(2-Hydroxyethoxy)phenoxy)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,4.27 g, 18.5 mmol), hydroquinone bis(2-hydroxyethyl) ether (10.6 g, 53.3mmol), N,N-dimethylaminopyridine (DMAP, 2.71 g, 22.2 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.34 g,48.7 mmol) and NEt₃ (13 mL, 93.3 mmol) in DMF (100 mL) was stirred atambient temperature overnight. The reaction mixture was evaporated todryness under vacuum and the residue was partitioned between HCl (3N,100 mL) and CH₂Cl₂ (200 mL). The organic layer was washed with water,brine, dried over Na₂SO₄, filtered and concentrated. The product wasseparated by silica gel column chromatography eluting with EtOAc/hexane(1:1, Rf=0.15) and then recrystalized from ethyl ether and hexane togive the title compound as a white solid (6.01 g, 31% yield). Mp 76–78°C. ¹H NMR (CDCl₃) δ 7.7–7.64 (m, 3H), 7.42–7.38 (m, 1H), 7.15–7.08 (m,2H), 6.74–6.72 (m 4H), 4.45–4.36 (m, 2H), 4.1–3.85 (m, 7H), 3.90 (s,3H), 2.13 (br. t, 1H), 1.58 (d, J=7.2 Hz, 3H). ¹³C NMR (CDCl₃) δ 174.6,157.5, 153.0, 152.8, 135.4, 133.6, 129.2, 128.8, 127.1, 126.1, 125.9,118.8, 115.7, 115.3, 105.5, 69.7, 66.6, 63.1, 61.4, 55.2, 45.2, 18.4.MS(API) m/z 428 (M+NH₄)⁺. Anal. calcd. for C₂₄H₂₆O₆: C, 70.23; H, 6.38.Found: C, 70.01; H, 6.39.

39b.2-(4-(2-(Nitrooxy)ethoxy)phenoxy)ethyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate

To a solution of Example 39a (3.76 g, 9.2 mmol) in CH₂Cl₂ (50 mL), wasadded NEt₃ (1.4 mL, 10.0 mmol) and methanesulfonyl chloride (0.9 mL,11.6 mmol) and stirred at ambient temperature for 2 hours. The reactionwas quenched with HCl (3N, 50 mL) and extracted with CH₂Cl₂ (50 mL×2).The combined extracts were washed with HCl (3N), water, brine, driedover Na₂SO₄, filtered, concentrated and dry under vacuum to give a crudeproduct, (methanesulfonate, that was used without purification).Tetrabutylammonium nitrate (5.61 g, 18.4 mmol.) was added to the crudeproduct and the mixture heated to reflux in toluene (100 mL) overnight.The reaction was cooled to ambient temperature and partitioned betweenethyl acetate (100 mL) and water (100 mL×4), dried over Na₂SO₄, filteredand concentrated. The product was separated by silica gel columnchromatography eluted with EtOAc/hexane (1:3, Rf=0.25) and thenrecrystalized from ethyl ether and hexane to obtained the title compoundas a white solid (2.17 g, 52% yield for 2 steps). Mp 67–69° C. ¹H NMR(300 MHz, CDCl₃) δ 7.7–7.64 (m, 3H), 7.42–7.38 (m, 1H), 7.14–7.08 (m,2H), 6.73–6.72 (m 4H), 4.79–4.75 (m, 2H), 4.41–4.37 (m, 2H), 4.17–4.01(m, 4H), 3.90 (s, 3H), 3.89 (q, J=7.2 Hz, 1H), 1.58 (d, J=7.2 Hz, 3H).¹³C NMR (75 MHz, CDCl₃) δ 174.5, 157.6, 153.2, 152.3, 135.4, 133.6,129.2, 128.8, 127.1, 126.2, 125.9, 118.9, 115.8, 115.5, 105.5, 71.1,66.6, 64.6, 63.1, 55.2, 45.2, 18.5. Mass spectrum (API-TIS) m/z 473(M+NH₄)⁺. Anal. calcd. for C₂₄H₂₅NO₈: C, 63.29; H, 5.53; N, 3.08. Found:C, 63.08; H, 5.38; N, 2.78.

Example 40 2-((2S)-2-(6-Methoxy(2-naphthyl))propanoyloxy)ethyl3-(nitrooxy)-propyl ethane-1,2-dioate 40a. 3-(Nitrooxy)propan-1-ol

A solution of 3-bromo-1-propanol (5.42 g, 39.0 mmol) in acetonitrile (20mL) was added to a solution of AgNO₃ (10.16 g, 59.8 mmol) inacetonitrile (50 mL) and stirred at room temperature for 24 hours. Tothe reaction mixture was added brine (350 mL) and stirred for 1 hour.The silver salts were filtered off through Celite and the filtrate wasextracted with Et₂O (200 mL×3). The organic layer was washed with brine,dried over Na₂SO₄, filtered, concentrated and dried under vacuum to givethe title compound (4.08 g, 86% yield, >95% purity) that was used in thenext step without purification. ¹H NMR (300 MHz, CDCl₃) δ 4.61 (t, J=6.4Hz, 2H), 3.78 (t, J=6.4 Hz, 2H), 1.99 (m, 2H). ¹³C NMR (75 MHz, CDCl₃) δ70.3, 58.5, 29.5.

40b. 2-Hydroxyethyl(2S)-2-(6-methoxy(2-naphthyl))-propanoate

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid sodium salt(10.9 g, 43.2 mmol) and 2-bromoethanol (27.11 g, 0.22 mol) in DMF (150mL) was heated to 80° C. for 3.5 hours. The excess 2-bromoethanol andDMF were evaporated under vacuum at 60° C. The resulted crude materialwas dissolved in CH₂Cl₂ (400 mL) and washed with water (400 mL),saturated NaHCO₃ (100 mL), 3N HCl (100 mL), brine and dried over Na₂SO₄,filtered and concentrated. Trituration of the residue with ether/hexanegave the title compound as a white solid (9.97 g, 84% yield). m.p.72–73° C. ¹H NMR (300 MHz, CDCl₃) δ 8.0–7.68 (m, 3H), 7.66–7.61 (m, 1H),7.16–7.1 (m, 2H), 4.25–4.15 (m, 2H), 3.93 (s, 3H), 3.92 (q, J=7.2 Hz,1H), 3.75–3.70 (m, 2H), 1.78 (br. t, 1H), 1.59 (d, J=7.2 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ 174.7, 157.3, 135.2, 133.4, 129.9, 128.6, 126.9,125.8, 125.6, 118.6, 105.3, 65.9, 60.3, 54.8, 45.0, 18.2. MS(API) m/z275 (M+NH₄)⁺.

40c. 2-((2S)-2-(6-Methoxy(2-naphthyl))propanoyloxy)ethyl3-(nitrooxy)propyl ethane-1,2-dioate

A solution of the product of Example 40a (1.36 g, 11.2 mmol) was addedto a mixture of oxalyl chloride (3 mL, 34.4 mmol) and Na₂CO₃ (2.86 g,27.0 mmol) in CH₂Cl₂ (50 mL) and stirred at ambient temperature for 3hours. The resulting mixture was evaporated to dryness under reducedpressure. A solution the product of Example 40b (2.78 g, 10.1 mmol) inCH₂Cl₂ (50 mL) was added to the resulted mixture and then heated toreflux for 2 hours. After cooled to ambient temperature, Na₂CO₃ wasremoved by filtration and washed with CH₂Cl₂ (100 mL). The filtrate waswashed with 3N HCl, water and brine, dried over Na₂SO₄, filtered, andconcentrated. The product was purified by silica gel columnchromatography eluting with EtOAc/hexane (2:3, Rf=0.25) to give thetitle compound as an oil (2.49 g, 55% yield). The oil solidified afterstanding for 2 weeks at ambient temperature. Mp 55–58° C. ¹H NMR (300MHz, CDCl₃) δ 7.7–7.64 (m, 3H), 7.4–7.35 (m, 1H), 7.15–7.08 (m, 2H),4.6–4.2 (m, 8H), 3.87 (s, 3H), 3.86 (q, J=7.2 Hz, 1H), 2.01 (m, 2H),1.56 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.1, 157.5, 156.8,135.1, 133.5, 129.1, 128.6, 127.0, 126.0, 125.8, 118.8, 105.3, 69.1,64.3, 62.7, 61.4, 55.1, 45.0, 25.7, 18.2. Mass spectrum (API-TIS) m/z467 (M+NH₄)⁺.

Example 41N-((2S)-2-(6-Methoxy(2-naphthyl))propanoylamino)-4(nitrooxy)butanamide41a.1,3-Dioxobenzo(c)azolidin-2-yl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A mixture of N-hydroxyphthalimide (7.1 g, 43.4 mmol),(2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 10 g, 43.4 mmol)and N,N-dimethylaminopyridine (DMAP, 5.3 g, 43.4 mmol) in CH₂Cl₂ (70 mL)and DMF (30 mL) at 0° C. was treated with1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (8.3 g,43.4 mmol) in CH₂Cl₂ (50 mL). The reaction mixture was stirred at roomtemperature for 16 hours and the solvent was evaporated under vacuum.The residue was then dissolved in EtOAc, washed with brine, dried overNa₂SO₄ and filtered. The residue after evaporation of the solvent waschromatographed on silica gel eluting with EtOAc hexane (1:1) to givethe title compound (7.6 g, 47% yield) as a white solid. Mp 110–112° C.¹H NMR (300 MHz, d₆-DMSO) δ 7.80–8.06 (m, 7H), 7.50 (dd, J=1.7 and 8.5Hz, 1H), 7.32–7.37 (m, 1H), 7.20 (dd, J=2.5 and 9.0 Hz, 1H), 4.50 (q,J=7.1 Hz, 1H), 3.89 (s, 3H), 1.64 (d, J=7.1 Hz, 3H). ¹³C NMR (75 MHz,d₆-DMSO) δ 171.2, 161.8, 157.5, 153.0, 135.5, 133.6, 133.5, 129.3,128.4, 128.2, 127.3, 126.1, 126.0, 124.0, 119.0, 105.8, 55.2, 41.8,18.6. Mass spectrum (API-TIS) m/z 376 (MH⁺), 393 (MNH₄ ⁺).

41b. (2S)-2-(6-Methoxy(2-naphthyl))propanohydrazide

Hydrazine monohydrate (1.7 g, 1.7 mL, 53.3 mmol) was added drop-wise toa solution of the product of Example 41a (5 g, 13.3 mmol) in CH₂Cl₂ (30mL) and methanol (2.4 mL) at room temperature. The resultant suspensionwas stirred at room temperature for 30 minutes. The residue afterevaporation of the solvent was dissolved in 5% Na₂CO₃, extracted withEtOAc. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and filtered. The residue after evaporation of the solvent waschromatographed on silica gel eluting with MeOH:EtOAc:hexane (0.1:1:1)to give the title compound (1.7 g, 52% yield) as a white solid. Mp106–108° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.69–7.78 (m, 3H), 7.45 (dd,J=1.6 and 8.4 Hz, 1H), 7.24–7.28 (m, 1H), 7.13 (dd, J=2.5 and 8.9 Hz,1H), 4.15–4.24 (bs, 2H), 3.85 (s, 3H), 3.65 (q, J=7.1 Hz, 1H), 1.41 (d,J=7.0 Hz, 3H). ¹³C NMR (75 MHz, d₆-DMSO) δ 172.9, 157.0, 137.2, 133.1,129.1, 128.3, 126.5, 125.3, 118.6, 105.6, 55.1, 43.2, 18.3. Massspectrum (API-TIS) m/z 245 (MH⁺).

41c.N-((2S)-2-(6-Methoxy(2-naphthyl))propanoylamino)-4-hydroxybutanamide

A mixture of γ-butyrolactone (0.78 g, 0.7 mL, 9.1 mmol) and the productof Example 41b (1.12 g, 4.57 mmol) in THF (3 mL) was heated at 120° C.for 3 hours. The precipitate was filtered. The residue after evaporationof the filtrate was chromatographed on silica gel eluting withMeOH:EtOAc:hexane (0.1:1:1) to give the title compound (0.25 g, 17%yield) as a white solid. Mp 149–151° C. ¹H NMR (300 MHz, d₆-DMSO) δ9.82–9.95 (bs, 1H), 9.45–9.60 (bs, 1H), 7.71–7.82 (m, 3H), 7.47 (d,J=8.6 Hz, 1H), 7.24–7.29 (m, 1H), 7.14 (dd, J=2.5 and 8.9 Hz, 1H), 4.45(t, J=5.2 Hz, 1H), 3.86 (s, 3H), 3.80 (q, J=7.0 Hz, 1H), 3.31–3.41 (m,2H), 2.12 (t, J=7.3 Hz, 2H), 1.56–1.70 (m, 2H), 1.43 (d, J=7.0 Hz, 3H).¹³C NMR (75 MHz, d₆-DMSO) δ 172.3, 171.1, 157.0, 136.7, 133.2, 129.1,128.3, 126.6, 125.4, 118.6, 105.7, 60.1, 55.2, 42.9, 29.9, 28.4, 18.4.Mass spectrum (API-TIS) m/z 329 (M−H), 331 (MH⁺), 313 (M−OH), 353(MNa⁺).

41d.N-((2S)-2-(6-Methoxy(2-naphthyl))propanoylamino)-4-(nitrooxy)butanamide

A suspension of the product of Example 41c (0.23 g, 0.69 mmol) in EtOAc(6.5 mL) was added drop-wise to a mixture of fuming HNO₃ (0.22 g, 146μL, 3.48 mmol) and Ac₂O (0.56 g, 0.53 mL, 5.56 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 1 hour, diluted with EtOAc andwashed with ice cold saturated NaHCO₃, water and dried over Na₂SO₄. Theresidue after filtration and evaporation was chromatographed on silicagel eluting with MeOH:EtOAc:hexane (0.1:1:1) to give the title compound(0.1 g, 38% yield) as a pale yellow solid. Mp 117–119° C. ¹H NMR (300MHz, CDCl₃) δ 8.95–9.11 (bs, 1H), 8.55–8.67 (bs, 1H), 7.62–7.74 (m, 3H),7.36 (dd, J=1.7 and 8.5 Hz, 1H), 7.06–7.18 (m, 2H), 4.38 (t, J=6.3 Hz,2H), 3.90 (s, 3H), 3.79 (q, J=7.1 Hz, 1H), 2.26 (t, J=6.9 Hz, 2H), 1.95(p, J=6.6 Hz, 2H), 1.60 (d, J=7.1 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ171.4, 168.5, 158.0, 135.0, 134.1, 129.4, 129.1, 127.8, 126.4, 126.1,119.5, 105.8, 72.1, 55.5, 44.9, 29.6, 22.5, 18.4. Mass spectrum(API-TIS) m/z 376 (MH⁺), 398 (MNa⁺).

Example 424-((2S)-2-(6-Methoxy(2-naphthyl))propanoyloxy)(2S,3S)-2,3-bis(nitrooxy)butyl(2S)-2-(6-methoxy(2-naphthyl))propanoateand(2S,3S)-2,3-Bis(nitrooxy)-4-hydroxybutyl(2S)-2-(6-methyoxy(2-naphthyl))propanoate42a. (2S,3S)-1,4-Bis(1,1,2,2-tetramethyl-1-silapropoxy)butane-2,3-diol

To L-threitol (4.8958 g, 40.090 mmol) and triethylamine (8.93 g, 88mmol) in DMF (100 mL) was added t-butyldimethylsilyl chloride. (12.0851g, 80.177 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 0.5 hour, and filtered. The filtrate was concentrated todryness. The resultant product was dissolved in EtOAc, washed withwater, and brine. The organic phase was dried over magnesium sulfate,filtered, and concentrated. The product was chromatographed on silicagel eluting with MeOH:CH₂Cl₂ (0:100, 0.5:99.5, 1:99, 2:98, 3:97) to givethe title compound (8.592 g, 61% yield). ¹H NMR (300 MHz, CDCl₃) δ3.77–3.70 (m, 6H), 2.87–2.84 (m, 2H), 0.90 (s, 18H), 0.08 (s, 12H). ¹³CNMR (75 MHz, CDCl₃) δ 71.4, 65.0, 25.8, 18.2, −5.47. APIMS: (IS, NH₄OAc)m/z 351 (M+H⁺), 368 (M+NH₄ ⁺), 373 (M+Na⁺), 718 (2M+NH₄ ⁺).

42b.(2S,3S)-(1,4-Bis(1,1,2,2-tetramethyl-1-silapropoxy))-(2,3-bis(nitrooxy))butane-2,3-diol

To acetic anhydride (22.7 g, 222 mmol) at 0° C. was slowly added fumingnitric acid (100%, 11.9 g, 189 mmol) over a period of 10 minutes. Theresultant solution was stirred at 0° C. for 0.5 hour. The product ofExample 42a (5.4119 g, 15.434 mmol) in THF (25 mL) was added. Thereaction mixture was stirred at room temperature for 50 minutes,concentrated. The product was treated with EtOAc, and washed with water.The organic phase was dried over magnesium sulfate, filtered, andconcentrated. The product was chromatographed on silica gel eluting withCH₂Cl₂:hexane (1:4) to give the title compound (6.40 g, 94% yield). ¹HNMR (300 MHz, CDCl₃) δ 5.41–5.39 (m, 2H), 3.90–3.89 (m, 4H), 0.89 (s,18H), 0.07 (s, 12H). ¹³C NMR (75 MHz, CDCl₃) δ 79.5, 60.2, 25.6, 18.1,−5.68. APIMS (IS, NH₄OAc) m/z 441 (M+H⁺), 458 (M+NH₄ ⁺), 898 (2M+NH₄ ⁺).

42c. (2S,3S)-2,3-Bis(nitrooxy)butane-1,4-diol

To the product of Example 42b (5.82 g, 13.21 mmol) in THF (150 mL) underargon at 0° C. was added acetic acid (2.99 mg, 49.8 mmol) and thentetrabutylammonium fluoride (1.0 M, 26.6 mmol). The reaction mixture wasstirred at room temperature for 1.5 hours, and concentrated to dryness.The resultant product was dissolved in EtOAc and washed with water, andbrine. The organic phase was dried over magnesium sulfate, filtered, andconcentrated. The resultant product was chromatrogrphed on silica geleluting with MeOH:CH₂Cl₂ (1.5:98.5, 3:97) to give the title compound(2.28 g, 81% yield). ¹H NMR (300 MHz, CDCl₃) δ 5.46–5.36 (m, 2H),4.07–3.96 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ 79.6, 60.2. APIMS (IS,NH₄OAc) m/z 230 (M+NH₄ ⁺). APIMS (IS, NH₄OAc) m/z 211 (M−H⁻).

42d.4-((2S)-2-(6-Methoxy(2-naphthyl))propanoyloxy)(2S,3S)-2,3-bis(nitrooxy)butyl(2S)-2-(6-methoxt(2-naphthyl))propanoateand(2S,3S)-2,3-Bis(nitrooxy)-4-hydroxybutyl(2S)-2-(6-methyoxy(2-naphthyl))propanoate

To the product of Example 42c (1.8502 g, 8.7224 mmol) in THF (50 mL) wasadded (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 2.305 g,10.010 mmol), N,N-dimethylaminopyridine (DMAP, 1.01 g, 8.21 mmol). Tothe resulting solution was added N,N-dicyclohexylcarbodiimide (2.07 g,10.02 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at roomtemperature overnight and filtered. The filtrate was concentrated todryness. The resultant product was dissolved in EtOAc, washed withcitric acid (0.2 M), brine died over magnesium sulfate, filtered, andconcentrated. The resultant product was chromatogrphed on silica geleluting with MeOH:CH₂Cl₂ (0:100, 0.5:99.5, 1:99, 1.5:98.5, 2:98) to give4-((2S)-2-(6-methoxy(2-naphthyl))propanoyloxy)(2S,3S)-2,3-bis(nitrooxy)butyl(2S)-2-(6-methoxt(2-naphthyl))propanoate (2.01 g, 36% yield) and(2S,3S)-2,3-bis(nitrooxy)-4-hydroxybutyl(2S)-2-(6-methyoxy(2-naphthyl))propanoate (1.25 g, 34% yield). ¹H NMR(300 MHz, CDCl₃) δ 7.70–7.67 (m, 4H), 7.60–7.59 (m, 2H), 7.31–7.26 (m,2H), 7.16–7.10 (m, 4H), 5.07–5.01 (m, 2H), 4.39–4.33 (m, 2H), 4.03–3.97(m, 2H), 3.91 (s, 6H), 3.80 (q, J=7.1 Hz, 2H), 1.59 (d, J=7.2 Hz, 6H).¹³C NMR (75 MHz, CDCl₃) δ 173.67, 157.8, 134.4, 133.8, 129.2, 128.8,127.4, 126.0, 125.8, 119.2, 105.6, 76.5, 60.2, 55.3, 45.1, 17.9. APIMS(IS, NH₄OAc) m/z 637 (M+H⁺), 654 (M+NH₄ ⁺), 659 (M+Na⁺). ¹H NMR (300MHz, CDCl₃) δ 7.73–7.69 (m, 2H), 7.64–7.63 (m, 1H), 7.37–7.33 (m, 1H),7.17–7.11 (m, 2H), 5.48–5.42 (m, 1H), 5.02–4.97 (m, 1H), 4.59 (dd,J=12.8 Hz & 3.6 Hz, 1H), 4.22 (dd, J=12.8 Hz & 5.2 Hz, 1H), 3.91 (s,3H), 3.91–3.84 (m, 1H), 3.77–3.64 (m, 2H), 1.99 (s, 1H), 1.54 (d, J=7.1Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.0, 157.8, 134.5, 133.8, 129.2,128.8, 127.4, 126.0, 125.8, 119.2, 105.6, 79.2, 76.9, 60.8, 59.7, 55.3,45.3, 17.9. APIMS (IS, NH₄OAc) m/z 425 (M+H⁺), 442 (M+NH₄ ⁺), 447(M+Na⁺).

Example 43 2-((3-((Nitrooxy)methyl)phenyl)carbonylamino)ethyl(2S)-2-(6-methoxy(2-napthyl propanoate 43a. 3-((Nitrooxy)methyl)benzoicacid

A solution of silver nitrate (12.98 g, 76.4 mmol) and3-(chloromethyl)benzoic acid (6.53 g, 76.4 mmol) in acetonitrile (160mL) was heated to 75° C. overnight. The reaction mixture was then cooledto ambient temperature and stirred with brine (100 mL) for 1 hour. Theresulting mixture was filtered through Celite and washed with water. Thefiltrate was concentrated and then extracted with CH₂Cl₂. The combinedorganic extracts were washed with water, brine, dried over Na₂SO₄,filtered, concentrated and dried under vacuum. The crude product waswashed with Et₂O/hexane (15:85) and then dried under vacuum to obtainthe title compound as a white solid (6.08 g, 80% yield). Mp 123–125° C.¹H NMR (300 MHz, CDCl₃) δ 8.18–8.14 (m, 2H), 7.68–7.57 (m, 1H), 7.55 (t,J=8.1 Hz, 1H), 5.50 (s, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 166.9, 133.6,133.0, 131.3, 130.1, 74.5. Mass spectrum (API-TIS) m/z 196 (M−H)⁻. Anal.calcd. for C₈H₇NO₅: C, 48.74; H, 3.58; N, 7.10. Found: C, 48.84; H,3.54; N, 6.85.

43b. 2-((tert-Butoxy)carbonylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,7.60 g, 33.0 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (5.30 g, 32.9mmol), N,N-dimethylaminopyridine (DMAP, 0.35 g, 2.86 mmol) and1,3-dicyclohexylcarbodiimide (6.80 g, 33.0 mmol) in CH₂Cl₂ (200 mL) wasstirred at ambient temperature overnight. The byproduct, dicyclohexylurea, was removed by filtration. The filtrate was concentrated,dissolved in EtOAc (50 mL) and then cooled in a dry-ice bath toprecipitate the remaining dicyclohexyl urea and then filtered. Thefiltrate was concentrated, dissolved in CH₂Cl₂ (15 mL) and hexane (200mL) and then stirred until the product precipitated. The solid was driedunder vacuum to give the title compound (10.12 g, 82% yield). Mp 82–84°C. ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.65 (m, 3H), 7.42–7.38 (m, 1H),7.16–7.11 (m, 2H), 5.05 (br, 1H), 4.13 (t, J=5.3 Hz, 2H), 3.91 (s, 3H),3.87 (q, J=7.1 Hz, 1H), 3.30 (br. q, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.45(s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 174.4, 157.6, 155.6, 135.4, 133.6,129.2, 128.8, 127.1, 126.0, 125.8, 119.0, 105.5, 79.3, 63.7, 55.2, 45.2,39.5, 28.2, 18.3. Mass spectrum (API-TIS) m/z 374 (MH)⁺. Anal. calcd.for C₂₁H₂₇NO₅: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.43; H, 7.16; N,3.66.

43c. 2-Aminoethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate hydrochloride

A solution of HCl/Et₂O (9.4 g/50 mL) was added to the product of Example43b (4.85 g, 13.0 mmol) and stirred at ambient temperature overnight.The resulted white solid was filtered and washed with Et₂O and thendried under vacuum to give the title compound (3.79 g, 94% yield). Mp184–186° C. ¹H NMR (300 MHz, d₆-DMSO) δ 8.28 (br, 3H), 7.83–7.74 (m,3H), 7.44 (dd, J=8.7, 1.8 Hz, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.16 (dd,J=9.0, 2.7 Hz, 1H), 4.31 (m, 1H), 4.13 (m, 1H), 3.99 (q, J=7.2 Hz, 1H),3.87 (s, 3H), 3.05 (br. q, 2H), 1.51 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz,d₆-DMSO) δ 173.9, 157.2, 135.5, 133.4, 129.2, 128.4, 127.0, 126.4,125.8, 118.8, 105.7, 60.9, 55.2, 44.3, 37.6, 18.4. Mass spectrum(API-TIS) m/z 274 (MH)⁺.

43d. 2-((3-((Nitrooxy)methyl)phenyl)carbonylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of the product of Example 43c (1.76 g, 5.7 mmol), the productof Example 43a (1.06 g, 5.4 mmol), N,N-dimethylaminopyridine (DMAP, 0.14g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.27 g, 6.6 mmol) and NEt₃ (2.5 mL, 17.9 mmol) in CH₂Cl₂(50 mL) was stirred at ambient temperature overnight. The reactionmixture was partitioned between 3N HCl (100 mL) and CH₂Cl₂ (200 mL×2).The combined organic extracts were back washed with water, brine, driedover Na₂SO₄ filtered, concentrated and dried under vacuum. The productwas separated by silica gel column chromatography eluting withEtOAc:hexane (1:1, Rf=0.22) to give the title compound as a white solid(0.46 g, 19% yield). Mp 92–94° C. ¹H NMR (300 MHz, CDCl₃) δ 7.63–7.58(m, 4H), 7.41–7.03 (m, 6H), 6.40 (br, 1H), 5.27 (s, 2H), 4.32–4.21 (m,2H), 3.88 (s, 3H), 3.87 (q, J=7.2 Hz, 1H), 3.29 (br. q, 2H), 1.56 (d,J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 174.8, 166.5, 157.6, 135.4,134.5, 133.5, 132.6, 131.5, 129.1, 128.8, 128.7, 127.6, 127.3, 127.2,126.3, 125.8, 125.7, 119.0, 105.5, 73.9, 63.1, 55.2, 45.2, 39.2, 18.1.Mass spectrum (API-TIS) m/z 453 (MH)⁺.

Example 44(2R)-2-(nitrooxy)-3-(phenylmethoxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate44a.(2R)-27hydroxy-3-(phenylmethoxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH₂Cl₂ (120 mL) wasstirred at ambient temperature overnight. The byproduct, dicyclohexylurea, was removed by filtration. The reaction mixture was partitionedbetween HCl (3N, 50 mL) and CH₂Cl₂ (50 mL×2). The combined organicextracts were back washed with water, brine, dried over Na₂SO₄,filtered, concentrated and dried under vacuum. The product was separatedby silica gel column chromatography eluting with EtOAc:hexane (1:2,Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers(88:12, 3.87 g). ¹H NMR (300 MHz CDCl₃) δ 7.69–7.64 (m, 3H), 7.40–7.03(m, 8H), 5.34 (s, 2H), 4.17–4.14 (m, 2H), 3.88 (s, 3H), 3.9–3.85 (m,2H), 3.33–3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ 174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2,128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5,73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS)m/z 412 (M+NH₄)⁺.

44b. (2R)-2-(nitrooxy)-3-(phenylmethoxy)propyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

The title compound can be prepared following the procedure for Example12.

Example 452-(N-Methyl(4-((nitrooxy)methyl)phenyl)carbonylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate45a. (tert-Butoxy)-N-(2-hydroxyethyl)-N-methylcarboxamide

2-(Methylamino)ethanol (7.5; g, 0.1 mol) was dissolved in anhydrous THF(250 mL) and to this solution at room temperature was addeddi-t-butyldicarbonate (19.5 g, 0.1 mol) in THF (50 mL). The reactionmixture was stirred at room temperature overnight. The solvent wasevaporated and the residue was extracted with EtOAc. The combinedorganic extracts were washed with water, brine, dried over sodiumsulfate, and filtered. The filtrate was evaporated to give the titlecompound (16.5 g) as a colorless thick oil, ¹HNMR (300 MHz, CDCl₃) δ3.66 (m, 2H), 3.31 (br t, J=4.4 Hz, 2H), 2.85 (s, 3H), 1.39 (s, 9H).

45b. 2-((tert-Butoxy)-N-methylcarbonylamino)ethyl (2S)-2-(6-methoxy(2naphthyl)) propanoate

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,11.51 g, 50 mmol) and the product of Example 45a (7.5 g, 50 mmol) inanhydrous CH₂Cl₂ (300 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC, 9.55 g,50 mmol) and N,N-dimethylaminopyridine (DMAP, 6.1 g, 50 mmol) at 0° C.under nitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 24 hours. The solvent was removed and the residue wasextracted with EtOAc, washed with water, brine, dried over sodiumsulfate, filtered and evaporated. The product was purified by columnchromatography on silica gel eluting with MeOH:CH₂Cl₂ (5:95) to give thetitle compound (17.1 g, 99% yield) as colorless thick oil. ¹HNMR (300MHz, CDCl₃) δ 7.69 (d, J=8.6 Hz, 2H), 7.64 (d, J=1.2 Hz, 1H), 7.05 (dd,J=8.5 and 1.2 Hz, 1H), 7.15 (m, 2H), 4.2 (m, 2H), 3.82 (s, 3H), 3.65 (q,J=7.2 Hz, 1H), 2.8 (m, 2H), 1.57 (d, J=7.2 Hz, 3H), 1.42 (s, 9H).

45c. 2-(Methylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

The product of the Example 45b (17.1 g, 50 mmol) was dissolved in CH₂Cl₂(400 mL). The solution was cooled to 0° C. and TFA (80 mL) was addeddrop-wise. The ice bath was removed and the reaction mixture was stirredat room temperature overnight, then the solvent was evaporated. Theresidue was treated with aqueous sodium carbonate (10%) and extractedwith EtOAc. The combined organic extracts were washed with water, brine,dried over sodium sulfate, and the solvent was evaporated. Triturationof the resulting solid with hexane gave the pure product as a whitesolid. Mp 64–68° C. ¹NMR (300 MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz, 2H), 7.66(d, J=1.3, 1H), 7.4 (dd, J=8.5 and 1.8 Hz, 1H), 7.18–7.08 (m, 2H), 4.18(t, J=5.4 Hz, 2H), 3.89 (s, 3H), 3.80 (q, J=7.1 Hz, 1H), 2.73 (t, J=5.4Hz, 2H), 2.31 (s, 3H), 1.56 (d, J=7.1 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ174.5, 157.6, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9,105.5, 63.9, 55.2, 50.0, 45.3, 36.0, 18.4.

45d.2-(N-methyl(4-((nitrooxy)methyl)phenyl)carbonylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of the product of Example 45c (1.0 g, 3.50 mmol) and theproduct of the Example 11a (1.03 g, 5.25 mmol) in anhydrous CH₂Cl₂ (17mL) N,N-dimethylaminopyridine (DMAP, 430 mg, 3.50 mmol) and1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 670mg, 3.50 mmol) were added successively and the reaction mixture wasstirred under an inert nitrogen atmosphere at room temperature for 5hours. The reaction mixture was diluted with CH₂Cl₂ then washed withsaturated aqueous NaHCO₃, aqueous KHSO₄ (5%), water, brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography eluting withEtOAC:hexane (2:8, 1:1) to give the title compound (490 mg, 30% yield)as a white solid. Mp 108–115° C. ¹H NMR (300 MHz, CDCl₃) δ 7.97 (d,J=8.1 Hz, 1H), 7.84 (d, J=8.2, 1H), 7.69–7.58 (m, 3H), 7.42 (d, J=8.4,1H), 7.36–7.26 (m, 2H), 7.13–7.07 (m, 2H) 5.41 (s, 2H), 4.49–4.45 (m,2H), 4.06–3.95 (m, 1H), 3.90 (s, 3H), 3.69–3.41 (m, 2H), 2.98 (s, 3H),1.50–1.46 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 174.1, 165.6, 157.6, 137.2,136.7, 133.5, 130.8, 130.0, 129.1, 129.1, 128.3, 127.5, 126.1, 125.7,118.9, 105.7, 73.6, 62.6, 55.3, 47.5, 43.5, 36.8, 20.6; LRMS (APIMS) m/z467 (M+H)⁺.

Example 46 (1S,2S,5S,6R)-6-(Nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl2-(1-((4 chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate

To a slurry of indomethacin (2.16 g, 6.04 mmol) and(2S)-7-(nitrooxy)-4,8-dioxabicyclo(3.3.0) octan-2-ol (isosorbide5-mononitrate, 1.21 g, 6.34 mmol, 1.05 eq) in CH₂Cl₂. (20 mL) at 0° C.were added were added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimidehydrochloride (EDAC, 1.27 g, 1.1 eq) and a catalytic amount ofN,N-dimethylaminopyridine (DMAP). The reaction mixture was stirred at 0°C. for 30 minutes, and then at room temperature overnight, diluted withCH₂Cl₂ and washed H₂O, brine, dried over sodium sulfate, filtered andevaporated to give an off-white solid. The solid was recrystallized fromCH₂Cl₂/EtOAc to give the title compound (2.0 g, 62% yield) as a whitesolid. Mp 159–160° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.66 (m, 2H), 7.48 (m,2H), 6.93 (m, 1H), 6.88 (m, 1H), 6.68 (m, 1H), 5.33 (m, 1H), 5.23 (m,1H), 4.91 (m, 1H), 4.41 (m, 1H), 3.95 (m, 4H), 3.83 (s, 3H), 3.68 (s,2H), 2.37 (s, 3H); LRMS (APIMS) m/z 531 (M+1)⁺, 548 (M+18)⁺.

Example 47 (1S,2S,5S,6R)-6-(Nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

To a slurry of diclofenac (101 g, 3.41 mmol) and(2S)-7-(nitrooxy)-4,8-dioxabicyclo(3.3.0) octan-2-ol (isosorbide5-mononitrate, 658 mg, 3.44 mmol, 1.01 eq) in CH₂Cl₂ (20 mL) at 0° C.were added dicyclohexylcarbodiimide (DCC, 3.58 mmol, 1.05 eq, 3.58 mL ofa 1M solution in methylene chloride) and a catalytic amount ofN,N-dimethylaminopyridine (DMAP). Dicyclohexylurea (DCU) precipitatedalmost immediately and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was filtration through asmall pad of Celite and the solid washed with CH₂Cl₂. The organicfiltrate was washed with HCl (1N), sodium bicarbonate, water, brine,dried over sodium sulfate, filtered and the solvent removed in vacuo togive a sticky yellow oil. The oil was purified by flash chromatographyon silica gel column eluted with CH₂Cl₂ to give the title compound (268mg, 17% yield) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ 7.34 (m, 2H),7.15 (m, 2H), 6.99 (m, 2H), 6.71 (bs, 1H), 6.57 (m, 1H), 5.35 (m, 1H),5.28 (m, 1H), 4.95 (m, 1H), 4.47 (m, 1H), 4.04 (m, 3H), 3.88 (m, 1H),3.83 (s, 2H); LRMS (APIMS) m/z 469 (M+1)⁺.

Example 482-(((4-Methylphenyl)sulfonyl)(2-(nitrooxy)ethyl)amino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate48a.2-((2-Hydroxyethyl)((4-methylphenyl)sulfonyl)amino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen,5.0 g, 21.7 mmol), N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide (16.89g, 65.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.530 g, 4.34 mmol)in CH₂Cl₂ (250 mL) and DMF (3 mL) at room temperature was added1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC,4.99 g, 26.05 mmol). The reaction mixture was stirred overnight at roomtemperature, and then partitioned between CH₂Cl₂ and HCl (1N). Theaqueous layer was washed with CH₂Cl₂ and the combined organic extractswere washed with water, brine, dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with EtOAC/hexane (1:1) to give the title compoundas a thick oil (7.15 g, 15.16 mmol, 70% yield): ¹H NMR (300 MHz, CDCl₃)δ 7.73 (d, J=8.6 Hz, 2H), 7.66 (m, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.40(dd, J=1.7, 8.5 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=2.5, 8.8Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 3.88 (q,J=7.2 Hz, 1H), 3.38 (m, 2H), 3.09 (t, J=5.1 Hz, 2H), 2.44 (s, 3H) 2.18(t, J=6.0 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z472 (MH⁺), 489 (M+18⁺).

48b:2-(((4-Methylphenyl)sulfonyl)(2-(nitrooxy)ethyl)amino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

To acetic anhydride (5.6 mL, 60.6 mmol) at 0° C. was added fuming nitricacid (90%, 1.77 mL, 37.9 mmol) with stirring. The resulting mixture wasstirred at room temperature for 25 min., then added drop-wise to asolution of the product of Example 48a, (7.15 g, 15.16 mmol) in EtOAc(20 mL) at 0° C. and was then stirred at 0° C. for 1 hour, and thenpoured into a 0° C. mixture of ethyl acetate (25 mL) and sodiumbicarbonate (50 mL). The mixture was stirred at 0° C. for 20 min., thenwarmed to room temperature for 1 hour, partitioned between ethyl acetateand water, washed with sodium bicrbonate, water, brine and dried oversodium sulfate. The solvent was removed in vacuo, and the residue waspurified by column chromatography on silica, eluting with EtOAc/hexane(1:1) to give the title compound as a pale yellow oil (6.92 g, 13.4mmol, 88% yield). The oil solidified, and was recrystallized fromdichloromethane/petroleum ether to give pale yellow needles. Mp 92–95°C. ¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=8.9 Hz, 2H), 7.63 (m, 1H), 7.62(d, J=8.2 Hz, 2H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H),7.27 (s, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 4.21(m, 4H), 3.93 (s, 3H), 3.82 (q, J=7.1 Hz, 1H), 3.38 (m, 2H), 3.14 (t,J=5.9 Hz, 2H), 2.42 (s, 3H), 1.57 (d, J=7.2 Hz, 3H). Mass spectrum(API-TIS) m/z 471 (M−NO2+H), 534 (M+18).

Example 492-(N-Methyl-2-(4-((nitrooxy)methyl)phenyl)acetylamino)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate

The title compound was prepared as a colorless oil (660 mg, 40% yield)from the product of Example 30a (1.10 g, 5.25 mmol) and the product ofExample 45c (1 g, 3.5 mmol) following the procedure for Example 48. ¹HNMR (300 MHz, CDCl₃) δ 7.72–7.65 (m, 4H), 7.57 (s, 2H), 7.25 (s, 1H),7.16–7.06 (m, 3H), 5.32 (s, 2H), 4.22–4.09 (m, 2H), 4.01–3.98 (m, 1H),3.90 (s, 3H), 3.75–3.69 (m, 2H), 3.54–3.45 (m, 2H), 2.68 (s, 3H),1.49–1.45 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 174.0, 170.7, 157.7, 136.8,135.2, 133.5, 131.0, 129.7, 129.4, 129.1, 128.3, 127.5, 126.2, 125.6,119.0, 105.7, 74.4, 62.9, 55.3, 47.5, 43.5, 40.9, 36.4, 20.6; LRMS(APIMS) m/z 481 (M+H)⁺.

Example 50 (2R)-2,3-Bis(nitrooxy)propyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate

To a solution of indomethacin (1.789 g, 5 mmol) and the product ofExample 5d (0.91 g, 5 mmol) in anhydrous CH₂Cl₂ (25 mL) were added1-ethyl-3-(3-dimethylaminopropyl) carbamide hydrochloride (EDAC) (0.96g, 5 mmol) and N,N-dimethylaminopyridine (DMAP, 0.61 g, 5 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredat room temperature overnight. The solvent was evaporated and theresidue was extracted with EtOAc, washed with water, brine, dried oversodium sulfate, filtered, and the organic extracts were evaporated. Theproduct was purified by column chromatography on silica gel eluting withEtOAc:hexane (1:4) to give the title compound (1.6 g, 62% yield) as acolorless thick oil. ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J=8.2 Hz, 2H),7.48 (d, J=8.2 Hz, 2H), 6.93 (s, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.69 (d,J=8.9 Hz, 1H), 5.41 (s, 1H), 4.60 (dd, J=12.7 and 3.2 Hz, 1H), 4.48 (m,2H), 4.25 (dd, J=12.3 and 5.9 Hz, 1H), 3.83 (s, 3H), 3.59 (s, 2H), 2.38(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 169.9, 168.2, 156.0, 139.3, 136.1,133.6, 131.1, 130.7, 130.1, 129.1, 128.2, 114.9, 111.6, 111.3, 100.9,75.9, 68.3, 60.8, 55.5, 29.8, 13.1; LRMS (APIMS) m/z 522 (MH⁺).

Example 51 (2S)-2,3-Bis(nitrooxy)propyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate51a. (2S)-2,3-Bis(nitrooxy)propan-1-ol

The title compound was prepared in four steps from((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol following theprocedures for Examples 5a, 5b, 5c, and 5d.

51b. (2S)-2,3-Bis(nitrooxy)propyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate

To a solution of indomethacin (1.789 g, 5 mmol) and the product ofExample 51a (0.91 g, 5 mmol) in anhydrous CH₂Cl₂ (25 mL) were added1-ethyl-3-(3-dimethylaminopropyl) carbamide hydrochloride (EDAC, 0.955g, 5 mmol) and N,N-dimethylaminopyridine (DMAP, 0.61 g, 5 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredat room temperature overnight. The solvent was evaporated and theresidue was extracted with EtOAc, washed with water, brine, dried oversodium sulfate, filtered, and the organic extracts were evaporated. Theproduct was purified by column chromatography on silica gel eluting withEtOAc:hexane (1:4) to give the title compound (1.6 g, 62% yield) as acolorless thick oil. ¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, J=8.5 Hz, 2H),7.46 (d, J=8.5 Hz, 2H), 6.91 (d, J=2.2 Hz, 1H), 6.85 (d, J=9.1 Hz, 1H),6.63 (dd, J=9.0 and 2.5 Hz, 1H), 5.45 (m, 1H), 4.60 (dd, J=12.6 and 3.7Hz, 1H), 4.45 (m, 2H), 4.25 (dd, J=12.6 and 5.6 Hz, 0.1H), 3.83 (s, 3H),3.65 (s, 2H), 2.38 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.0, 168.2,156.1, 139.4, 136.2, 133.6, 131.1, 130.7, 130.2, 129.1, 128.2, 115.0,111.6, 111.4, 100.9, 75.9, 68.3, 60.9, 55.6, 29.9, 13.2; LRMS (APIMS)m/z 522 (MH⁺).

Example 52(2S)-2,3-Bis(nitrooxy)propyl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

To a solution of diclofenac (1.47 g, 5 mmol) and the product of Example51a (0.91 g, 5 mmol) in anhydrous CH₂Cl₂ (25 mL) were added1-ethyl-3-(3-dimethylaminopropyl) carbamide hydrochloride (EDAC, 0.955g, 5 mmol) and N,N-dimethylaminopyridine (DMAP, 0.61 g, 5 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredat room temperature overnight. The solvent was evaporated and theresidue was extracted with ethyl acetate, washed with water, brine,dried over sodium sulfate, filtered, and the organic extracts wereevaporated. The product was purified by column chromatography on silicagel eluting with EtOAc:hexane (1:9) to give the title compound (1 g, 43%yield) as colorless thick oil. ¹H NMR (300 MHz, CDCl₃) δ 7.35 (d, J=9.2Hz, 2H), 7.2 (m, 2H), 7.0 (m, 2H), 6.6 (m, 2H), 5.5 (m, 1H), 4.75 (dd,J=12.2 and 3.9 Hz, 1H), 4.65–4.5 (m, 2H), 4.35 (dd, J=12.3 and 5.9 Hz,1H), 3.87 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 171.5, 142.5, 137.5, 130.7,129.3, 128.8, 128.3, 124.2, 123.3, 118.5, 76.0, 68.4, 61.1, 37.8; LRMS(APIMS) m/z 460 (MH⁺).

Example 53 (2R)-2,3-bis(nitrooxy)propyl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

To a solution of diclofenac (1.47 g, 5 mmol) and the product of Example5d (0.91 g, 5 mmol) in anhydrous CH₂Cl₂ (25 mL) were added1-ethyl-3-(3-dimethylaminopropyl) carbamide hydrochloride (EDAC) (0.955g, 5 mmol) and N,N-dimethylaminopyridine (DMAP, 0.61 g, 5 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredat room temperature overnight. The solvent was evaporated in vacuo andthe residue was extracted with ethyl acetate, washed with water, brine,dried over sodium sulfate, filtered, and the organic extracts wereevaporated. The product was purified by column chromatography on silicagel eluting with EtOAc:hexane (1:9) to give the title compound (0.5 g,22% yield) as colorless thick oil. ¹H NMR (300 MHz, CDCl₃) δ 7.4 (d,J=9.2 Hz, 2H), 7.25 (d, J=7.4 Hz, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.03 (t,J=8.1 Hz, 1H), 6.6 (s, 1H), 6.61 (d, J=8.0 Hz, 1H), 5.5 (m, 1H), 4.72(dd, J=12.9 and 3.4 Hz, 1H), 4.5 (m, 2H), 4.35 (dd, J=12.6 and 3.6 Hz,1H), 3.89 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 171.5, 142.5, 137.5, 130.7,129.3, 128.8, 128.3, 124.2, 123.5, 122.3, 118.5, 76.0, 68.4, 61.1, 37.8;LRMS (APIMS) m/z 460 (MH⁺).

Example 54(2S)-2-(6methoxy(2-naphthyl))-1-(4-(nitrooxy)butylthio)propan-1-one 54a.(2S)-1-(4-Hydroxybutylthio)-2-(6-methoxy(2-naphthyl))propan-1-one

To a solution of naproxen (5.03 g, 21.9 mmol), 4-mercapto-1-butanol(2.32 g, 21.9 mmol) and N,N-dimethylaminopyridine (DMAP) (0.534 g, 4.37mmol) in dichloromethane (200 mL) at room temperature was added1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC)(5.03 g, 26.2 mmol) as a solid, in portions. The reaction mixture wasstirred for 3 hours at room temperature, then partitioned betweendichloromethane and water, and the water layer was washed with moredichloromethane. The combined organic layer was washed with water andbrine, then dried over magnesium sulfate. The solution was concentratedunder vacuum, and the residue was purified via column chromatography,50% ethyl acetate/hexane. The appropriate fractions were combined, andthe solvent removed by rotary evaporation to give an oil, 2.647 g, whichcontained 19% 4-mercapto-1-butanol by weight (product weight 2.07 g, 6.5mmol, 30% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J=2.7 Hz, 1H), 7.71(d, J=2.3 Hz, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H),7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 4.02 (q, J=7.1 Hz,1H), 3.92 (s, 3H), 3.61–3.64 (m, 2H), 2.87 (m, 2H), 1.61 (d, J=7.1 Hz,3H), 1.59 (m, 2H), 1.41 (m, 2H); mass spectrum (API-TIS) m/z 319 (M+H⁺),336 (M+18⁺).

54b.(2S)-2-(6-methoxy(2-naphthyl))-1-(4-(nitrooxy)butylthio)propan-1-one

To acetic anhydride (3.45 mL, 37.2 mmol) at 0° C. was added fumingnitric acid (90%, 1.01 mL, 23.3 mmol) with stirring. After addition wascomplete, the mixture was stirred at room temperature for 25 min., thenadded dropwise to a solution of the product of Example 54a, (2.547 g,15.5 mmol) in ethyl acetate (20 mL) at −10° C. The reaction mixture wasstirred at −10° C. for 15 min., then quenched with 5 mL of saturatedsodium bicarbonate. The mixture was stirred cold for 20 min., thenwarmed to room temperature for 1 h. The reaction mixture was partitionedbetween ethyl acetate and water, washed with sodium biacrbonate, water,and brine, and dried over sodium sulfate. The solvent was removed byrotary evaporation, and the residue was purified by columnchromatography on silica, eluting with 25% ethyl acetate/hexane to givethe nitrate as a pale yellow oil (1.17 g, 50% yield). The oil slowlysolidified in the freezer. M.p. 30–35° C.; ¹H NMR (300 MHz, CDCl₃) δ7.73 (s, 1H), 7.70 (s, 1H), 7.68 (s, 1H), 7.38 (dd, J=1.7, 8.5 Hz, 1H),7.15 (dd, J=2.5, 8.9 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 4.39 (t, J=6.7 Hz,2H), 4.01 (q, J=7.1 Hz, 1H), 3.91 (s, 3H), 2.86 (t, J=6.7 Hz, 2H),1.65–1.74 (m, 4H), 1.61 (d, J=7.1 Hz, 3H); mass spectrum (API-TIS) m/z318 (M−NO2⁺), 364 (M+H⁺), 381 (M+18⁺).

Example 55 (N-Methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate 55a((tert-Butyl)oxycarbonyl)methyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate

To a solution of indomethacin (6.388 g, 18 mmol) in anhydrous DMF (45mL) were successively added NaHCO₃ (1.4 g, 16.7 mmol) andtert-butylbromoacetate (2.95 g, 15 mmol) at room temperature undernitrogen atmosphere. The reaction mixture was stirred at roomtemperature for 2 days. The reaction mixture was then poured overice-cold water, stirred, and the white solid obtained was filtered off,washed with water and dried. The product was recrystallized fromEtOAc:hexane (1:4) to give the title compound (7.06 g, 88% yield) as awhite soild. Mp 96–97° C. ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J=8.5 Hz,2H), 7.45 (d, J=8.5 Hz, 2H), 7.0 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz,1H), 6.6 (dd, J=9.0 and 2.4 Hz, 1H), 4.52 (s, 2H), 3.83 (s, 3H), 3.77(s, 2H), 2.37 (s, 3H), 1.44 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 170.1,168.2, 166.6, 156.2, 139.2, 136.0, 133.8, 131.1 (2×C), 130.7, 130.5,129.0 (2×C), 114.9, 112.1, 111.9, 101.1, 82.4, 61.5, 55.6, 29.7, 27.9,13.4; LRMS (APIMS) m/z 472 (MH⁺).

55b.2-(2-(1-((4-Chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetyloxy)aceticacid

The product of Example 55a (6.12 g, 13 mmol) was dissolved in CH₂Cl₂ (50mL) and TFA (15 mL) was added. The reaction mixture was stirred at roomtemperature for 2 days. The solvent and TFA were evaporated in vacuo andthe residue obtained was dissolved in EtOAc (50 mL) and the solventevaporated again to remove traces of trifluoroacetic acid. The residueobtained was recrystallized from EtOAc:hexane (1:4) to give the titlecompound (4.3 g, 80% yield) as a gray colored solid. Mp 137–138° C. ¹HNMR (300 MHz, CDCl₃) δ 8.93 (br s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.45 (d,J=8.4 Hz, 2H), 6.96 (d, J=2.3 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 6.6 (dd,J=9.0 and 2.4 Hz, 1H), 4.67 (s, 2H), 3.81 (s, 3H), 3.78 (s, 2H), 2.36(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.6, 170.3, 168.4, 155.9, 139.2,136.1, 133.7, 131.1 (2×C), 130.7, 130.4, 129.1 (2×C), 114.9, 111.8,111.7, 101.2, 60.5, 55.6, 29.6, 13.4; LRMS (APIMS) m/z 416 (MH⁺).

55c (N-Methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate

The product of Example 17c (457 mg, 2.5 mmol) was stirred in CH₂Cl₂ (10mL) and Et₃N (0.25 mL) was added at room temperature and the reactionmixture was stirred for 10 minutes. Then the product of Example 55b(1.04 g, 2.5 mmol) in CH₂Cl₂ (10 mL) was added followed by1-ethyl-3-(3-dimethylaminopropyl) carbamide hydrochloride (EDAC, 0.483g, 2.5 mmol) and N,N-dimethylaminopyridine (DMAP, 0.305 g, 2.5 mmol).The resulting solution was stirred under nitrogen atmosphere at roomtemperature overnight. The reaction mixture was diluted with EtOAc,washed with water, aqueous NaHCO₃, water, 0.5 N HCl, brine, dried oversodium sulfate, filtered, and the organic extracts were evaporated. Theproduct was purified by column chromatography on silica gel eluting withEtOAc:hexane (1:1) to give the title compound (1.1 g, 85% yield) aswhite foam. Mp 118–122° C. ¹H NMR (300 MHz, CDCl₃) δ 7.65 (d, J=8.4 Hz,2H), 7.45 (d, J=8.5 Hz, 2H), 7.0 (d, J=2.2 Hz, 1H), 6.87 (d, J=9.0 Hz,1H), 6.65 (dd, J=9.0 and 2.3 Hz, 1H), 4.73 (s, 2H), 4.58 (t, J=5.1 Hz,2H), 3.83 (s, 3H), 3.81 (s, 2H), 3.67 (t, J=5.1 Hz, 2H), 2.99 (s, 3H),2.36 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.4, 168.2, 166.7, 156.0,139.1, 136.0, 133.8, 131.1 (2×C), 130.6, 130.5, 129.0 (2×C), 114.8,112.0, 111.8, 101.1, 70.9, 61.5, 55.6, 46.0, 35.6, 29.7, 13.3; LRMS(APIMS) m/z 534 (MH⁺).

Example 56 (N-(2-(Nitrooxy)ethyl)carbamoyl)methyl2-(1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)acetate

The product of Example 22a, 2-(nitrooxy)ethylammonium nitrate (850 mgs,5 mmol) and the product of Example 55b (1.68 g, 4 mmol) were reactedwith 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC, 4mmol) and N,N-dimethylaminopyridine (DMAP, following the procedure forExample 55c. The product was purified by column chromatography on silicagel eluting with EtOAc:hexane (1:1) to give the title compound (1.22 g,60% yield) as white solid. Mp 128–129° C. ¹H NMR (300 MHz, CDCl₃) δ 7.65(d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 6.96 (d, J=2.2 Hz, 1H), 6.87(d, J=9.0 Hz, 1H), 6.7 (dd, J=9.0 and 2.3 Hz, 1H), 6.1 (d, J=5.1 Hz,2H), 4.56 (s, 2H), 4.32 (d, J=5.1 Hz, 2H), 3.81 (s, 3H), 3.77 (s, 2H),3.37 (q, J=5.2 Hz, 2H), 2.38 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 168.9,168.2, 167.3, 156.1, 139.5, 136.3, 133.5, 131.1 (2×C), 130.8, 130.1,129.1 (2×C), 115.3, 111.4, 101.0, 70.9, 62.8, 55.7, 36.4, 30.1, 13.3;LRMS (APIMS) m/z 504 (MH⁺) and 521 (MNH₄ ⁺).

Example 57 (N-(2-(Nitrooxy)ethyl)carbamoyl)methyl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate 57a. Oxycarbonylmethyl2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

To a solution of diclofenac (7.7 g, 26 mmol) in anhydrous DMF (60 mL)were successively added NaHCO₃ (2.8 g, 33.4 mmol) andtert-butylbromoacetate (5.07 g, 26 mmol) at room temperature undernitrogen atmosphere, and the reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated under reduced pressureand the residue obtained was triturated with a mixture of 20%ethylacetate in hexane to give the title compound (10.1 g) as a whitesoild in quantitative yield. Mp 83–84° C. ¹H NMR (300 MHz, CDCl₃) δ 7.33(d, J=8.5 Hz, 2H), 7.25 (m, 1H), 7.12 (d, J=5.5 Hz, 1H), 6.96 (m, 2H),6.78 (br s, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.56 (s, 2H), 3.92 (s, 2H),1.35 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 171.3, 166.4, 142.7, 137.8,130.9, 129.5, 128.8, 128.0, 124.0, 123.9, 122.0, 118.3, 82.6, 61.7,38.1, 27.8.

57b. Oxycarbonylmethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate

The product of Example 57a (0.3 g, 0.73 mmol) was dissolved indichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added. Thereaction mixture was stirred at room temperature for 7 h. The solventand trifluoroacetic acid were evaporated in vacuo and the residueobtained was purified by flash column chromatography over silica gelusing 40% ethylacetate in hexane to give the title compound (0.15 g, 57%yield) as a white solid. Mp 107–111° C. ¹H NMR (300 MHz, CDCl₃) δ 7.33(d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.13 (t, J=5.5 Hz, 1H), 6.95(m, 2H), 6.6 (br s, 1H), 6.53 (d, J=8.5 Hz, 1H), 4.71 (s, 2H), 3.80 (s,2H); LRMS (APIMS) m/z 3,54 (MH⁺).

57c. (N-(2-(Nitrooxy)ethyl)carbamoyl)methyl2-(2-((2,6-dichlorophenyl)amino) phenyl)acetate

The product of Example 22a, 2-(nitrooxy)ethylammonium nitrate (132 mgs,0.84 mmol) and the product of example 57b (150 mg, 0.42 mmol) werereacted using EDAC (80 mg, 0.42 mmol) and DMAP (51 mg, 0.42 mmol)following the procedure as described in example 55c. The product waspurified by column chromatography over silica gel using 20% ethylacetate in hexane to give the title compound (23 mg, 13% yield) as awhite solid, mp 81–83° C. ¹H NMR (300 MHz, CDCl₃) δ 7.35 (d, J=8.5 Hz,2H), 7.28 (dd, J=8.4 and 2,2 Hz, 1H), 7.18 (dt, J=5.5 and 2.2 Hz, 1H),7.1–7.0 (m, 2H), 6.54 (d, J=8.4 Hz, 1H), 6.41 (br s, 1H), 6.08 (m, 1H),4.60 (s, 2H), 4.41 (t, J=5.5 Hz, 2H), 3.91 (s, 2H), 3.48 (q, J=5.5 Hz,2H); ¹³C NMR (75 MHz, CDCl₃) δ 170.2, 167.2, 142.4, 137.2, 130.8, 129.7,128.9, 128.5, 124.5, 124.6, 123.0, 122.2, 118.2, 71.1, 63.0, 138.1,36.4; LRMS (APIMS) m/z 442 (MH⁺).

Example 58 Comparative In Vivo Antiinflammatory and Gastric LesionActivities

The rat paw edema test was used to measure the antiinflammatoryactivity. The rat paw edema test was performed according to the methodof Winter et al, Proc. Soc. Exp. Biol. Med. 111: 544–547, 1962. MaleSprague-Dawley rats (250–275 g) were fasted overnight and dosed by oralgavage with vehicle or suspensions of compound one hour prior to thesubplantar injection of 50 μl of 1% suspension of carrageenan. Threehours later, the paw volume was measured and compared with the initialvolume measured immediately after carrageenan injection.

The rat gastric lesion test, described by Kitagawa et al, J. Pharmacol.Exp. Ther., 253:1133–1137 (1990), and Al-Ghamdi et al, J. Int. Med.Res., 19:2242 (1991), was used to evaluate the activity of compounds toproduce gastric lesion. Male Sprague Dawley rats (Charles RiverLaboratories, Wilmington, Mass.) weighing 230–250 g were used for theexperiments. The rats were housed with laboratory chow and water adlibitum prior to the study. The rats were fasted for 24 hours with freeaccess to water and then dosed by oral gavage with vehicle or with testcompounds given at a volume of 0.5 mL/100 g. Food was withheld after theinitial dosing. Rats were euthanized by CO₂ three hours after dosing.The stomachs were dissected along the greater curvature, washed with adirected stream of 0.9% saline and pinned open on a sylgard based petridish for examination of the hemorrhagic lesion. Gastric lesion score wasexpressed in mm and calculated by summing the length of each lesion.

Table 1 shows the relative activities of compounds in the analgesic,antiinflammatory and gastric lesion tests, and are expressed as theratio of activity relative to the parent NSAID. The results show thatthe nitrosated NSAIDs have either comparable antiinflammatory activitiescompared to their parent NSAID molecule. Table 1 also shows that thenitrosated NSAIDs of the invention have significantly and unexpectedlydecreased gastric lesion activities.

TABLE 1 Relative Activity Compound Antiinflammation Gastric LesionVehicle 1 <0.01 Naproxen 0.55   1 Example 1 0.46   0.32 Example 2 0.49  0.11 Example 4 0.92   0.04 Example 5 0.45   0,21 Example 6 0.45   0.09Example 7 0.85 Not determined Example 9 0.69   0.02 Example 11 0.82 Notdetermined Example 12 0.47   0.18 Example 13 0.51   0.55 Example 14 0.78  0.15 Example 18 0.60   0.25 Example 19 0.60   0.30 Example 20 0.63  0.03 Example 21 0.48   0.19 Example 23 0.87 Not determined Example 260.75   0.07 Example 27c 0.57   0.20 Example 27d 0.72 Not determinedExample 28 0.57 Not determined Example 31 0.61   0.06 Example 32 0.58  0.06 Example 33 0.60   0.07 Example 34 0.60   0.02 Example 35 0.06 Notdetermined Example 36 0.65   0.57 Example 37 0.56   0.72 Example 39 0.70  0.04 Example 41 0.86 Not determined

The disclosure of each patent, patent application and publication citedor described in the specification is hereby incorporated by referenceherein in its entirety.

Although the invention has been set forth in detail, one skilled in theart will appreciate that numerous changes and modifications can be madeto, the invention, and that such changes and modifications may be madewithout departing from the spirit and scope of the present invention.

1. A compound of Formula (I), or a pharmaceutically acceptable saltthereof; wherein the compound of Formula (I) is:

 wherein: R_(m) is a hydrogen or a lower alkyl group; R_(n) is:

s is an integer of 0 or 1; X is:(1)—Y—(CR₄R₄′)_(p)—V—B-T-(CR₄R₄′)_(p)—ONO₂;(2)—Y—(CR₄R₄′)_(p)-T-C(O)—(CR₄R₄′)_(o)—(CH₂)—ONO₂;(3)—Y—(CR₄R₄′)_(p)-T-(CH₂)_(q)-V-(CR₄R₄′)_(q)—(CH₂)—ONO₂;(4)—Y—(CR₄R₄′)_(p)—V—(CH₂₎ _(q)—V—(CR_(4R) ₄′)_(q)—(CH₂)—ONO₂; (5)—Y—(CR₄R₄′)_(o)(W)_(q)—(CR₄R₄′)_(o)—(CH₂)—ONO₂; (6)—Y—(CR₄R₄′)_(p)—V—(CH₂)_(o)—(W)_(q)—(CR₄R₄′)_(q)—(CH₂)—ONO₂; (7)—Y—(CR₄R₄′)_(p)—(W)_(q)-(T)_(o)-(CR₄R₄′)_(o)—(CH₂)—ONO₂; (8)—Y—(CR₄R₄′)_(q)—C(Z)-V—(CR₄R₄′)_(q)—(CH₂)—ONO₂; (9)—Y—(CR₄R₄′)_(p)—V—(CR₄R₄′)_(p)—(CH₂)—ONO₂; or (10)—Y—(CR₄R₄′)_(p)—V—(CH₂)_(q)-(T)_(o)-(CR₄R₄′)_(q)—(CH₂)—ONO₂; R₄ and R₄′at each occurrence are independently a hydrogen, lower alkyl group, —OH,—CH₂OH, —ONO₂, —NO₂ or —CH₂ONO₂; or R₄ and R₄′ taken together with thecarbon atom to which they are attached are a cycloalkyl group or aheterocyclic ring; V is —C(O)-T-, -T-C(O)—, -T-C(O)-T or T-C(O)—C(O)-T;W is a covalent bond or a carbonyl group; T at each occurrence isindependently an oxygen, (S(O)_(o))_(o) or NR_(j); R_(j) is a hydrogen,an alkyl group, an aryl group, a heterocyclic ring, an alkylcarbonylgroup, an alkylaryl group, an alkylsulfinyl group, an alkylsulfonylgroup, an arylsulfinyl group, an arylsulfonyl group, a sulfonamidogroup, a N-alkylsulfonamido group, a N,N-diarylsulfonamido group, aN-arylsulfonamido group, a N-alkyl-N-arylsulfonamido group, acarboxamido group or a hydroxyl group; p at each occurrence isindependently an integer from 1 to 6; q at each occurrence isindependently an integer from 1 to 3; o at each occurrence isindependently an integer from 0 to 2; Y is oxygen or sulfur (—S—); B iseither phenyl or (CH₂)_(o); Q′ is a cycloalkyl group, a heterocyclicring or an aryl group; Z is (═O), (═N—OR₅), (═N—NR₅R′₅) or (═CR₅R′₅); Mand M′ are each independently —O⁻ H₃N⁺—(CR₄R′₄)_(q)—CH₂ONO₂ or-T-(CR₄R′₄)_(o)—CH₂ONO₂; R₅ and R₅′ at each occurrence are independentlya hydrogen, a hydroxyl group, an alkyl group, an aryl group, analkylsulfonyl group, an arylsulfonyl group, a carboxylic ester, analkylcarbonyl group, an arylcarbonyl group, a carboxamido group, analkoxyalkyl group, an alkoxyaryl group, a cycloalkyl group or aheterocyclic ring; and with the proviso that for X in the compounds ofFormulas (I): when Y is oxygen or sulfur in Formula 5, and W is acovalent bond, at least one R₄ or R₄′ must be —OH, —ONO₂, —NO₂ or—CH₂ONO₂ or R₄ and R₄′ taken together with the carbon atom to which theyare attached are a cycloalkyl group or a heterocyclic ring; when Y isoxygen or sulfur in Formula 7, T is N(CH₃), W is a covalent bond and R₄and R₄′ are hydrogen, p cannot be the integer 2, and o cannot be theinteger 1 in —(CR₄R′₄)_(o); when Y is oxygen or sulfur in Formula 7, Wis a covalent bond, T is oxygen and o is the integer 1, at least one R₄or R₄′ must be —OH, —NO₂ or —CH₂ONO₂ or R₄ and R₄′ taken together withthe carbon atom to which they are attached are a cycloalkyl group or aheterocyclic ring.
 2. A composition comprising the compound of claim 1and a pharmaceutically acceptable carrier.
 3. The compound of claim 1,wherein X is:

wherein: Y′ is oxygen or sulfur; T′ is oxygen, sulfur or NR₆; X₅ isoxygen, (S(O)_(o))_(o) or NR₆; R₆ is a hydrogen, a lower alkyl group, anaryl group; n′ and m′ are each independently an integer from 0 to 10;and o is as defined herein.
 4. The compound of claim 1, wherein thecompound of Formula (I) is substituted with at least one —NO₂ group. 5.A compound selected from the group consisting of(N-methyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;(N-ethyl-N-(2-(nitrooxy)ethyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;(N-methyl-N-(((2-(nitrooxy)ethyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;(N-methyl-N-(((3-(nitrooxy)propyl)oxycarbonyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;(N-methyl-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;((2-(nitrooxy)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate;(N-(3-(nitrooxy)propyl)carbamoyl)methyl2-(6-methoxy-2-naphthyl)propanoate;((2-((2-(nitrooxy)ethyl)sulfonyl)ethyl)oxycarbonyl)methyl2-(6-methoxy-2-naphthyl)propanoate;(2S)-2-(6-methoxy(2-naphthyl))-N-((N-(2-(nitrooxy)ethyl)carbamoyl)methoxy)propanamide; (N-methyl-N-(3-(nitrooxy)propyl)carbamoyl)methyl(2S)-2-(6-methoxy(2-naphthyl))propanoate;2-((2S)-2-(6-methoxy(2-naphthyl))propanoyloxy)ethyl 3-(nitrooxy)-propylethane- 1,2-dioate; N-((2S)-2-(6-methoxy(2-naphthyl))propanoylamino)-4(nitrooxy)butanamide; or a pharmaceutically acceptable salt thereof. 6.A composition comprising at least one compound of claim 5 and apharmaceutically acceptable carrier.